Compounds and methods for degrading casein kinase 1 alpha

Abstract

Provided are novel compounds represented by Formula (I) which degrade CK1α (casein kinase 1 alpha), and methods of degrading CK1α, or preventing or treating blood cancer by administering the compounds to a subject in need thereof.

Description

COMPOUNDS AND METHODS FOR DEGRADING CASEIN KINASE 1 ALPHA BACKGROUND OF THE INVENTION

[0001] Casein kinase 1 alpha (CK1α) is a serine / threonine protein kinase involved in various cellular pathways and functions, including Wnt signaling, NF-κB signaling, p53 pathway, autophagy, and cell cycle. Inhibition of CK1α or reduction of its expression level has been demonstrated to induce cell death in several types of cancer, such as acute myeloid leukemia (AML) and diffuse large B cell lymphoma (DLBCL).

[0002] For instance, it has been reported that CK1α inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing CK1α as a therapeutic target for the treatment of AML (Jaras et al., J. Exp. Med.2014 Vol.211 No.4605-612). In addition, it was reported that in AML and multiple myeloma (MM), inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities (Janovska et al., Int. J. Mol. Sci. 2020, 21, 9026). In particular, it was previously found that CK1α controls signaling pathways involved in proliferation, survival and stress in MM (Manni et al., Journal of Hematology & Oncology (2017) 10:157). Furthermore, it has been reported that CK1α is overexpressed in AML patients and acts as a negative element in the prognosis of AML patients, and thus CK1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis, and the targeting of CK1α and autophagy may offer a therapeutic opportunity to treat AML (Xu et al., ONCOLOGY REPORTS 44: 1895-1904, 2020). It has been also previously found that CK1α governs antigen-receptor-induced NF-kB activation and human lymphoma cell survival.

[0003] Therefore, CK1α has been known in the art as a target for preventing or treating blood cancer such as leukemia, lymphoma, and myeloma. Therefore, there has been a demand for developing CK1α-degraders or inhibitors which may be used for preventing or treating blood cancer such as leukemia, lymphoma, and myeloma. SUMMARY OF THE INVENTION

[0004] The present disclosure provides novel compounds which are represented by Formula (I) as follows, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0005] Such a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or prodrug thereof is useful for reducing CK1α protein levels and for treating or preventing blood cancer.

[0006] In Formula (I), in some embodiment, R1is C1-C8alkyl, C3-C8alkenyl, C3-C8alkynyl, C3-C8cycloalkyl or C5-C10bicycloalkyl each optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl, optionally substituted C6-C10aryl, C1-C3alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C5-C10 bicycloalkyl or optionally substituted C3-C6heterocycloalkyl.

[0007] In some embodiment, X is a bond or –(CH2)n– optionally substituted with one or more halogen, OH, O-C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl or C1-C6alkyl, wherein the C1-C6alkyl group may be taken together with the atom to which it is attached to form a C3-C6spiro alkyl ring, and wherein the –(CH2)n– group may contain 0-1 double bond or triple bond.

[0008] In some embodiment, n is an integer from 1 to 6.

[0009] In some embodiment, A is a bond, C4-C8cycloalkyl, C5-C10bicycloalkyl, C5-C10heterobicycloalkyl or C3-C8heterocycloalkyl each optionally substituted with one of more halogen, OH, O-C1-C3alkyl, CN, C1-C3haloalkyl, C1-C3alkyl or C3-C5cycloalkyl.

[0010] In some embodiment, Y is a bond or a –(CH2)m–.

[0011] In some embodiment, m is an integer of 1 or 2.

[0012] In some embodiment, Z is H or halogen.

[0013] In some embodiment, R2is -NR12R5, -NHC(O)R6, -NHC(O)NR8(R9), - C(O)NHR5, five or six-membered heteroaryl, or C3-C8heterocycloalkyl or C5-C10heterobicycloalkyl ring optionally substituted with one of more halogen, OH, O-C1-C3alkyl, CN, C1-C3haloalkyl, C1-C3alkyl or C3-C5cycloalkyl.

[0014] In some embodiment, R5is H, C1-C5alkyl, C3-C7cycloalkyl, five or six- membered heteroaryl, C5-C10bicycloalkyl, (C3-C6cycloalkyl)-C1-C3alkyl, (C3-C6heterocycloalkyl)-C1-C3alkyl, (C6-C10aryl)-C1-C3alkyl, (C1-C5-heteroaryl)-C1-C3alkyl or C3-C7heterocycloalkyl each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl, CH3SO2-, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C7heterocycloalkyl or C(O)NR8(R9).

[0015] In some embodiment, R6is C1-C6alkyl, C3-C6cycloalkyl or C3-C6heterocycloalkyl each optionally substituted with one or more halogen, C1-C3haloalkyl, optionally substituted C3-C6cycloalkyl, or NR8(R9).

[0016] In some embodiment, R8and R9are each independently H, substituted C1-C3alkyl or taken together with the nitrogen to which they are attached to form a 4-6 membered heterocyclic ring optionally substituted with one or more halogen or C1-C3haloalkyl.

[0017] In some embodiment, R12is H, C1-C5alkyl, or taken together with R5and the nitrogen to which it is attached to form (i) C3-C8cycloalkyl or heterocycloalkyl ring or (ii) C5- C10bicycloalkyl or heterobicycloalkyl ring, each optionally substituted with one or more halogen, C1-C3haloalkyl, OH, O-(C1-C3alkyl), O-(C1-C3haloalkyl) or CN.

[0018] In some embodiment, each stereocenter in the compound of Formula (I) is independently the R-enantiomer, the S-enantiomer or a mixture of R- and S- enantiomers.

[0019] In some embodiment, each double bond in the compound of Formula (I) is independently cis or trans.

[0020] In some embodiment, the compound is represented by Formula (I-a), (I-a) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0021] In Formula (I-a), in some embodiment, X is a bond or –(CH2)n–.

[0022] In some embodiment, R1is C1-C8alkyl or C3-C8cycloalkyl each optionally substituted with one or more halogen, OH, NH2, C1-C3alkyl, C1-C3haloalkyl, O-(C1-C3alkyl), optionally substituted C6aryl, optionally substituted C3-C8cycloalkyl, optionally substituted C3- C6heterocycloalkyl or optionally substituted C6-C8bicycloalkyl.

[0023] In some embodiment, A is C4-C6cycloalkyl, C4-C6heterocycloalkyl or C5-C7bicycloalkyl each optionally substituted with one or more halogen, OH, C1-C3alkyl or C1-C3haloalkyl.

[0024] In some embodiment, Y is a bond or -CH2-.

[0025] In some embodiment, R5is H, C1-C5alkyl, C3-C6cycloalkyl, 6-membered heteroaryl, C5bicycloalkyl, (C3-C4cycloalkyl)-C1-C2alkyl, (C3-C4heterocycloalkyl)-C1-C2alkyl, (C6aryl)-C1-C2alkyl, (C5heteroaryl)-C1-C2alkyl or C3-C4heterocycloalkyl each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl, CH3SO2- or C(O)NR8(R9).

[0026] In some embodiment, R12is H, C1-C5alkyl, or taken together with R5and the nitrogen to which it is attached to form a C3-C8heterocycloalkyl ring optionally substituted with one or more halogen or C1-C3haloalkyl.

[0027] In some embodiment, the compound is represented by Formula (I-b), (I-b) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0028] In Formula (I-b), in some embodiment, X is a bond or –(CH2)n–.

[0029] In some embodiment, R1is C3-C6alkyl optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl.

[0030] In some embodiment, A is bond or C4-C6cycloalkyl optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl.

[0031] In some embodiment, Y is a bond.

[0032] In some embodiment, R6is C1-C6alkyl, optionally substituted with NR8(R9).

[0033] In some embodiment, the compound is represented by Formula (I-c),(I-c) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0034] In Formula (I-c), in some embodiment, X is a bond or –(CH2)n–.

[0035] In some embodiment, R1is C1-C6alkyl optionally substituted with optionally substituted C3-C8cycloalkyl or optionally substituted C3-C6heterocycloalkyl.

[0036] In some embodiment, A is bond, C4-C6cycloalkyl, C4-C6heterocycloalkyl or C5- C7bicycloalkyl each optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl.

[0037] In some embodiment, Y is a bond.

[0038] In some embodiment, R5is H or C1-C3alkyl.

[0039] In some embodiment, the compound is represented by Formula (I-d), (I-d) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0040] In Formula (I-d), in some embodiment, R1is C1-C3alkyl optionally substituted with optionally substituted C3-C6cycloalkyl.

[0041] In some embodiment, A is optionally substituted C4-C6cycloalkyl.

[0042] In some embodiment, R2is C1-C4alkyl or (C3-C4cycloalkyl)-C1-C2alkyl, each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl or CH3SO2-.

[0043] In Formula (I), In some embodiment, each X and Y is a bond; A is C4-C6cycloalkyl; R1is C1-C3alkyl optionally substituted with optionally substituted C3-C6cycloalkyl; and R2is 5-membered heteroaryl.

[0044] In some embodiment, the compound is selected from the following Table A.

[0045] [Table A]

[0046] In some embodiment, the compound of the present disclosure is for use in degrading and / or reducing casein kinase 1 alpha (CK1α).

[0047] In some embodiment, the compound of the present disclosure is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

[0048] In some embodiment, the compound of the present disclosure is for use in preventing or treating blood cancer.

[0049] In some embodiment, the compound of the present disclosure is for manufacture of medicament for treatment of blood cancer.

[0050] In some embodiment, the present disclosure provides a pharmaceutical composition comprising: the compound of the present disclosure (represented by Formula (I), (I- a), (I-b) or (I-c)), or the pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0051] In some embodiment, the pharmaceutical composition is for use in degrading and / or reducing casein kinase 1 alpha (CK1α).

[0052] In some embodiment, the pharmaceutical composition is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

[0053] In some embodiment, the pharmaceutical composition is for use in preventing or treating blood cancer.

[0054] In some embodiment, the blood cancer is leukemia, lymphoma, or myeloma.

[0055] The present disclosure also provides a method of degrading and / or reducing casein kinase 1 alpha (CK1α) in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present disclosure.

[0056] The present disclosure also provides a method of inhibiting casein kinase 1 alpha (CK1α) activity in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present disclosure.

[0057] The present disclosure also provides a method of preventing or treating blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present disclosure.

[0058] In some embodiment, the blood cancer is leukemia, lymphoma, or myeloma.

[0059] In some embodiment, the leukemia is selected from the group consisting of acutemyeloid leukemia (AML), acute lymphoblastic leukemia or acute lymphocytic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), Large granular lymphocytic leukemia, adult T- cell leukemia, chronic eosinophilic leukemia (CEL) and myelodysplastic syndrome (MDS).

[0060] In some embodiment, the lymphoma is selected from the group consisting of Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system (CNS) lymphoma and peripheral T-cell lymphoma.

[0061] In some embodiment, the myeloma is selected from the group consisting of multiple myeloma, light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma and immunoglobulin E (IgE) myeloma. DETAILED DESCRIPTION OF THE INVENTION

[0062] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0063] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0064] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0065] All publications and patents cited in this specification are cited to disclose and describe the methods and / or materials in connection with which the publications are cited. All such publications and patents are herein incorporated by references as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials described in the cited publications and patents and does not extend to any lexicographical definitions from the cited publications and patents. Any lexicographical definition in the publications and patents cited that is not also expressly repeated in the instant application should not be treated as such and should not be read as defining any terms appearing in the accompanying claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

[0066] The present disclosure describes novel compounds which are represented by Formula (I) as follows, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof. In addition, the present disclosure describes an analog or a radical form of compounds represented by Formula (I). (I)

[0067] In Formula (I), in some embodiment, R1is C1-C8alkyl, C3-C8alkenyl, C3-C8alkynyl, C3-C8cycloalkyl or C5-C10bicycloalkyl each optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl, optionally substituted C6-C10aryl, C1-C3alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C5-C10bicycloalkyl or optionally substituted C3-C6heterocycloalkyl.

[0068] In some embodiment, X is a bond or –(CH2)n– optionally substituted with one or more halogen, OH, O-C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl or C1-C6alkyl, wherein the C1-C6alkyl group may be taken together with the atom to which it is attached to form a C3-C6spiro alkyl ring, and wherein the –(CH2)n– group may contain 0-1 double bond or triple bond.

[0069] In some embodiment, n is an integer from 1 to 6.

[0070] In some embodiment, A is a bond, C4-C8cycloalkyl, C5-C10bicycloalkyl, C5-C10heterobicycloalkyl or C3-C8heterocycloalkyl each optionally substituted with one of more halogen, OH, O-C1-C3alkyl, CN, C1-C3haloalkyl, C1-C3alkyl or C3-C5cycloalkyl.

[0071] In some embodiment, Y is a bond or a –(CH2)m–.

[0072] In some embodiment, m is an integer of 1 or 2.

[0073] In some embodiment, Z is H or halogen.

[0074] In some embodiment, R2is -NR12R5, -NHC(O)R6, -NHC(O)NR8(R9), - C(O)NHR5, five or six-membered heteroaryl, or C3-C8heterocycloalkyl or C5-C10heterobicycloalkyl ring optionally substituted with one of more halogen, OH, O-C1-C3alkyl, CN, C1-C3haloalkyl, C1-C3alkyl or C3-C5cycloalkyl.

[0075] In some embodiment, R5is H, C1-C5alkyl, C3-C7cycloalkyl, five or six- membered heteroaryl, C5-C10bicycloalkyl, (C3-C6cycloalkyl)-C1-C3alkyl, (C3-C6heterocycloalkyl)-C1-C3alkyl, (C6-C10aryl)-C1-C3alkyl, (C1-C5-heteroaryl)-C1-C3alkyl or C3-C7heterocycloalkyl each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl, CH3SO2-, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C7heterocycloalkyl or C(O)NR8(R9).

[0076] In some embodiment, R6is C1-C6alkyl, C3-C6cycloalkyl or C3-C6heterocycloalkyl each optionally substituted with one or more halogen, C1-C3haloalkyl, optionally substituted C3-C6cycloalkyl, or NR8(R9).

[0077] In some embodiment, R8and R9are each independently H, substituted C1-C3alkyl or taken together with the nitrogen to which they are attached to form a 4-6 membered heterocyclic ring optionally substituted with one or more halogen or C1-C3haloalkyl.

[0078] In some embodiment, R12is H, C1-C5alkyl, or taken together with R5and the nitrogen to which it is attached to form (i) C3-C8cycloalkyl or heterocycloalkyl ring or (ii) C5- C10bicycloalkyl or heterobicycloalkyl ring, each optionally substituted with one or more halogen, C1-C3haloalkyl, OH, O-(C1-C3alkyl), O-(C1-C3haloalkyl) or CN.

[0079] In some embodiment, each stereocenter in the compound of Formula (I) is independently the R-enantiomer, the S-enantiomer or a mixture of R- and S- enantiomers.

[0080] In some embodiment, each double bond in the compound of Formula (I) is independently cis or trans.

[0081] In some embodiment, the compound is represented by Formula (I-a), (I-a) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0082] In Formula (I-a), in some embodiment, X is a bond or –(CH2)n–.

[0083] In some embodiment, R1is C1-C8alkyl or C3-C8cycloalkyl each optionally substituted with one or more halogen, OH, NH2, C1-C3alkyl, C1-C3haloalkyl, O-(C1-C3alkyl), optionally substituted C6aryl, optionally substituted C3-C8cycloalkyl, optionally substituted C3- C6heterocycloalkyl or optionally substituted C6-C8bicycloalkyl.

[0084] In some embodiment, A is C4-C6cycloalkyl, C4-C6heterocycloalkyl or C5-C7bicycloalkyl each optionally substituted with one or more halogen, OH, C1-C3alkyl or C1-C3haloalkyl.

[0085] In some embodiment, Y is a bond or -CH2-.

[0086] In some embodiment, R5is H, C1-C5alkyl, C3-C6cycloalkyl, 6-membered heteroaryl, C5bicycloalkyl, (C3-C4cycloalkyl)-C1-C2alkyl, (C3-C4heterocycloalkyl)-C1-C2alkyl, (C6aryl)-C1-C2alkyl, (C5heteroaryl)-C1-C2alkyl or C3-C4heterocycloalkyl each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl, CH3SO2- or C(O)NR8(R9).

[0087] In some embodiment, R12is H, C1-C5alkyl, or taken together with R5and the nitrogen to which it is attached to form a C3-C8heterocycloalkyl ring optionally substituted with one or more halogen or C1-C3haloalkyl.

[0088] In some embodiment, the compound is represented by Formula (I-b), (I-b) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0089] In Formula (I-b), in some embodiment, X is a bond or –(CH2)n–.

[0090] In some embodiment, R1is C3-C6alkyl optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl.

[0091] In some embodiment, A is bond or C4-C6cycloalkyl optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl.

[0092] In some embodiment, Y is a bond.

[0093] In some embodiment, R6is C1-C6alkyl, optionally substituted with NR8(R9).

[0094] In some embodiment, the compound is represented by Formula (I-c), (I-c) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0095] In Formula (I-c), in some embodiment, X is a bond or –(CH2)n–.

[0096] In some embodiment, R1is C1-C6alkyl optionally substituted with optionally substituted C3-C8cycloalkyl or optionally substituted C3-C6heterocycloalkyl.

[0097] In some embodiment, A is bond, C4-C6cycloalkyl, C4-C6heterocycloalkyl or C5- C7bicycloalkyl each optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl.

[0098] In some embodiment, Y is a bond.

[0099] In some embodiment, R5is H or C1-C3alkyl.

[0100] In some embodiment, the compound is represented by Formula (I-d), (I-d) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

[0101] In Formula (I-d), in some embodiment, R1is C1-C3alkyl optionally substituted with optionally substituted C3-C6cycloalkyl. For example, C3-C6cycloalkyl can be substituted with one or more halogen, CN, OH, C1-C3alkyl, O-(C1-C3haloalkyl), O-(C1-C3alkyl) or C1-C3haloalkyl.

[0102] In some embodiment, A is optionally substituted C4-C6cycloalkyl. For example, A can be substituted with one or more halogen, CN, OH, C1-C3alkyl, O-(C1-C3haloalkyl), O- (C1-C3alkyl) or C1-C3haloalkyl.

[0103] In some embodiment, R2is C1-C4alkyl or (C3-C4cycloalkyl)-C1-C2alkyl, each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl or CH3SO2-. For example, R2is C1-C3alkyl optionally substituted with one or more halogen, O-(C1-C3haloalkyl), O-(C1-C3alkyl) or C1-C3haloalkyl.

[0104] In Formula (I), In some embodiment, each X and Y is a bond; A is C4-C6cycloalkyl; R1is C1-C3alkyl optionally substituted with optionally substituted C3-C6cycloalkyl; and R2is 5-membered heteroaryl.

[0105] The present disclosure describes novel compounds which are represented by Formula (I) as follows, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof. In addition, the present disclosure describes an analog or a radical form of compounds represented by Formula (I).

[0106] As used herein, the term "compound" unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof where applicable, in context. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds. The term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder.

[0107] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or may be stereoisomeric mixtures, and include all diastereomeric, and enantiomeric forms. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. Likewise, it is understood that, in any compound described, all tautomeric and conformeric forms are also intended to be included. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) of atoms about a rotating bond.

[0108] As used herein, any “R” group(s) represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionallysubstituted” or “substituted” group may be individually and independently substituted with one or more group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclyl(alkyl), hydroxy, alkoxy, cycloalkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, amino (including mono- substituted amino and di- substituted amino), and alkylamino. When a group is not described as “optionally substituted,” “unsubstituted” or “substituted,” such group is unsubstituted unless the definition of such group states otherwise.

[0109] As used herein, “Cato Cb” or “Ca-Cb” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, aryl, heteroaryl, heterocycloalkyl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the aryl, ring of the heterocycloalkyl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms.

[0110] As used herein, the term “alkyl” refers to a saturated monovalent chain of carbon atoms, which may be optionally branched. It is understood that in embodiments that include alkyl, illustrative variations of those embodiments include lower alkyl, such as C1-C8, C1-C6, C1- C5, C1-C4, C1-C3alkyl, methyl, ethyl, propyl, 3-methylpentyl, and the like.

[0111] As used herein, the term “alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C3, C3-C4, C3-C5, C3-C6, C3-C7, C3-C8, C4, C4-C5, C4-C6, C4-C7, C4-C8, C5, C5-C6, C5-C7, C5-C8, C6, C6-C7, C6-C8, C7, C7-C8, and C8. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1.4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3- hexadienyl, 1,4-hexadienyl, 1.5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be optionally substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, alkoxy, haloalkyl, carboxy, amido, nitro, oxo, and cyano.

[0112] As used herein, the term “alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include anynumber of carbons, such as C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C3, C3-C4, C3-C5, C3- C6, C3-C7, C3-C8, C4, C4-C5, C4-C6, C4-C7, C4-C8, C5, C5-C6, C5-C7, C5-C8, C6, C6-C7, C6-C8, C7, C7-C8, and C8. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 1,3-hexadiynyl, 1,4- hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be optionally substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, alkoxy, haloalkyl, carboxy, amido, nitro, oxo, and cyano.

[0113] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by one or more halogen atom(s). The term “Cn-mhaloalkyl” or “Cn-Cmhaloalkyl” refers to a Cn-malkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1} halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0114] As used herein, the term “cycloalkyl” refers to a monovalent chain of carbon atoms, a portion of which forms a ring. It is understood that in embodiments that include cycloalkyl, illustrative variations of those embodiments include lower cycloalkyl, such as C3-C8, C3-C7, C3-C6, C3-C5, C4-C8, C4-C7, C4-C6cycloalkyl, cyclopropyl, cyclohexyl, 3- ethylcyclopentyl, and the like.

[0115] As used herein, the term “bicycloalkyl” refers to two cycloalkyl groups, defined hereinabove, connecting with each other to form a bridged, fused or spiro bicyclic compound.

[0116] As used herein, the term “fused bicycloalkyl” refers to two cycloalkyl groups which share two adjacent atoms. In other words, the rings share one covalent bond, i.e. the so- called bridgehead atoms are directly connected.

[0117] As used herein, the term “bridged bicycloalkyl” refers to two cycloalkyl groups of which moieties have more than two atoms in common. That is, two rings do not share adjacent carbon atoms, but share three or more atoms, separating the two bridgehead atoms by a bridgecontaining at least one atom. Examples include, but are not limited to, bicyclo[3.2.1]heptyl (“norbornyl”), bicyclo[2.2.2]octyl, and the like.

[0118] As used herein, the term “spirobicycloalkyl” refers to bicyclic groups in which the two rings are attached at a single carbon atom that is a member of each of the two rings. The term includes both spirobicycloalkyls, in which the two rings are cycloalkyl rings attached at a single carbon atom that is a member of each of the two rings, and spirobicycloheteroalkyls, in which one ring is a heterocyclyl ring and the other ring is a cycloalkyl ring attached at a single carbon atom that is a member of each of the two rings, or in which both rings are heterocyclyl rings attached at a single carbon atom that is a member of each of the two rings. Examples of spirobicyclyl groups include spiro[3.3]heptenyl, spiro[3.4]octanyl, azaspiro[3.3]heptanyl, oxaazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, and azaspiro[3.4]octanyl.

[0119] As used herein, “heterocycloalkyl” refers to a non-aromatic ring, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. Heterocycloalkyl groups can include mono- or polycyclic (e.g., fused, bridged, or spiro) ring systems. Heterocycloalkyl also includes one or more aromatic rings fused to the non-aromatic heterocycloalkyl ring. The ring-forming carbon atoms of a heterocycloalkyl group can be optionally substituted by oxo. The ring-forming heteroatoms of the heterocycloalkyl group can be oxidized to form an N-oxide or a sulfonyl group. It is understood that in embodiments that include heterocycloalkyl, illustrative variations of those embodiments include lower cycloalkyl, such as C3-C8, C3-C7, C3-C6, C3-C5, C4-C8, C4-C7, C4-C6heterocycloalkyl and the like. Examples of heterocycloalkyl group include morpholine ring, pyrrolidine ring, piperazine ring, piperidine ring, tetrahydropyran ring, tetrahyropyridine, azetidine ring, tetrahydrofuran, etc.

[0120] As used herein, “heterobicycloalkyl” refers to a bicycloalkyl structure, which is unsubstituted or substituted, in which at least one carbon atom is replaced with a heteroatom independently selected from oxygen, nitrogen, and sulfur.

[0121] As used herein, the term “aryl” refers to an aromatic carbon ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of carbon ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representativearyl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be optionally substituted with one or more moieties selected from alkyl, alkenyl, alkynyl, haloalkyl, halo, hydroxy, amino, alkylamino, alkoxy, haloalkyl, carboxy, alkyl carboxylate, amido, nitro, oxo, and cyano.

[0122] As used herein, the term “heteroaryl” refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups that have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms independently selected from O, S, and / or N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic group are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic heteroaryl groups must include only aromatic rings. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents. Examples of monocyclic heteroaryl are, but not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, and other similar groups. Examples of bicyclic heteroaryl are, but not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, puropyridinyl, oxochromene, dioxoisoindolin, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl, and other similar groups.

[0123] In some embodiment, the compound is selected from the following Table A.

[0124] [Table A]

[0125] In some embodiment, the compound of the present disclosure is for use in degrading and / or reducing casein kinase 1 alpha (CK1α).

[0126] In some embodiment, the compound of the present disclosure is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

[0127] In some embodiment, the compound of the present disclosure is for use in preventing or treating blood cancer.

[0128] In some embodiment, the present disclosure provides a pharmaceutical composition comprising: the compound of the present disclosure (represented by Formula (I), (I-a), (I-b) or (I-c)), or the pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0129] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0130] The term “pharmaceutically acceptable carrier” is used herein to refer to a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise-undesirable, and is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier” as used in the specification and claims can include both one and more than one such carrier. By “pharmaceutically acceptable” it is meant the carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0131] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included aresalts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0132] The compounds represented by Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof degrade casein kinase 1 alpha (CK1α).

[0133] In some embodiment, the pharmaceutical composition is for use in degrading and / or reducing casein kinase 1 alpha (CK1α).

[0134] In some embodiment, the pharmaceutical composition is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

[0135] In some embodiment, the pharmaceutical composition is for use in preventing or treating blood cancer.

[0136] In some embodiment, the blood cancer is leukemia, lymphoma, or myeloma.

[0137] The present disclosure also provides a method of degrading and / or reducing casein kinase 1 alpha (CK1α) in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present disclosure.

[0138] The present disclosure also provides a method of inhibiting casein kinase 1 alpha (CK1α) activity in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present disclosure.

[0139] The present disclosure also provides a method of preventing or treating blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the present disclosure.

[0140] As used herein, the term “blood cancer” refers to cancer that begins in blood- forming tissue, such as the bone marrow, or in the cells of the immune system. In some embodiment, the “blood cancer” can include any cancer involving uncontrolled proliferation of blood cells, in particular white blood cells.

[0141] In some embodiment, the blood cancer is leukemia, lymphoma (Hodgkin and non-Hodgkin lymphomas), or myeloma.

[0142] In some embodiment, the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia or acute lymphocytic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia(HCL), T-cell prolymphocytic leukemia (T-PLL), Large granular lymphocytic leukemia, adult T- cell leukemia, chronic eosinophilic leukemia (CEL) and myelodysplastic syndrome (MDS).

[0143] In some embodiment, the lymphoma is selected from the group consisting of Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system (CNS) lymphoma and peripheral T-cell lymphoma.

[0144] In some embodiment, the myeloma is selected from the group consisting of multiple myeloma, light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma and immunoglobulin E (IgE) myeloma.

[0145] In some embodiments, the compounds of the present disclosure may bind to cereblon (CRBN), altering the specificity of the complex to induce the ubiquitination and degradation of CK1α, transcription factors essential for proliferative disorders such as multiple myeloma growth.

[0146] In some embodiments, the present disclosure provides compounds and compositions comprising an E3 ligase binding moiety that can bind to an E3 ligase (e.g., CRBN) and target protein binding moiety that can bind to a target protein, which results in the ubiquitination of a target protein and leads to degradation of the target protein by the proteasome.

[0147] As used herein, the term “degrade” or “degradation” as used herein means the degradation of a target protein mediated by an E3 ligase, for example, CRBN, resulting in a reduction of the protein levels. In one embodiment, the target protein can be Casein Kinase 1 (CK1, e.g., CK1α, CK1β1, CK1γ1, CK1γ2, CK1γ3, CK1δ, CK1ε) protein. In certain embodiments, the target protein preferably can be CK1α.

[0148] The term “CK1α” as used herein refers to Casein Kinase lα, a kinase in humans that is encoded by the CSNK1A1 gene. CK1α has been shown to play a critical role in the biology of AML (Jaras M et al, J Exp Med.2014; 211(4):605— 612).

[0149] As used herein, the term “effective amount” refers to that amount of an active agent being administered sufficient to degrade CK1α and / or inhibit CK1α activity. In certainembodiments, the term “effective amount” refers to that amount of an active agent being administered sufficient to treat a CK1α related disease, preferably blood cancer.

[0150] As used herein, the term “treat,” “treatment,” or “treating,” refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.

[0151] As used herein, the term “preventing” refers to a slowing of the disease or of the onset of the disease or the symptoms thereof. Preventing a disease or disorder can include stopping the onset of the disease or symptoms thereof.

[0152] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or excipients, or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0153] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0154] Multiple techniques of administering a compound, salt and / or composition exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound described herein, including a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof, can be administered orally.

[0155] One may also administer the compound, salt and / or composition in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.

[0156] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and / or salt described herein formulated in a compatible pharmaceutical excipient may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0157] The compounds, salt and / or pharmaceutical composition can be provided to an administering physician or other health care professional in the form of a kit. The kit is a package which houses a container which contains the compound(s) in a suitable pharmaceutical composition, and instructions for administering the pharmaceutical composition to a subject. The kit can optionally also contain one or more additional therapeutic agents. The kit can also contain separate doses of a compound(s) or pharmaceutical composition for serial or sequential administration. The kit can optionally contain one or more diagnostic tools and instructions for use. The kit can contain suitable delivery devices, for example., syringes, and the like, along with instructions for administering the compound(s) and any other therapeutic agent. The kit can optionally contain instructions for storage, reconstitution (if applicable), and administration ofany or all therapeutic agents included. The kits can include a plurality of containers reflecting the number of administrations to be given to a subject.

[0158] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.

[0159] The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between about 0.01 mg and 3,000 mg of each active ingredient, preferably between about 1 mg and 700 mg, e.g., about 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0160] In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50or Id50values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0161] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.

[0162] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for about 10 to 90% of the time, preferably between about 30 to 90% and most preferably between about 50 to 90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0163] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0164] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, theskilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and / or regime. EXAMPLES I. Synthesis of Compounds

[0165] Hydrochloride Salt Form of Compound 1

[0166] 3-(4-((4-Aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0167] Step-1: tert-Butyl (4-oxobutyl) carbamate A solution of oxalyl chloride (5.4 mL, 63.49 mmol, 1.2 equiv) in DCM (50 mL) was added dropwise to a solution of DMSO (10 mL, 1 vol) in DCM (100 mL, 10 vol) at -78°C over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. To this a solution of tert-Butyl (4-hydroxybutyl)carbamate 1 (10 g, 52.91 mmol, 1 equiv) in DCM (50 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for30 minutes at -78°C, was added N, N-diisopropylethylamine (29.2 mL, 158.7 mmol, 3 equiv) in drops at -78°C. Once addition was complete, the reaction mixture was slowly warmed to 0°C and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, 2: 8 / EtOAc: pet ether, Rf~ 0.6, KMnO4), the reaction mixture was diluted with DCM (200 mL) and washed with 10% aq citric acid solution (1 × 100 mL), water (1 × 200 mL) and brine (1 × 200 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30°C to afford tert-butyl (4-oxobutyl) carbamate (10 g, crude) as pale yellow liquid which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 6.84 (s, 1H), 2.89-2.93 (m, 2H), 2.42-2.44 (m, 2H), 1.60-1.64 (m, 2H), 1.38 (s, 9H).

[0168] Step-2: tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate A mixture of tert-Butyl (4-oxobutyl) carbamate 2 (9.0 g, 0.0484 mol, 1.8 equiv) and Lenolidamide 3 (CAS # 191732-72-6, 7.0 g, 0.0269 mol, 1 equiv) were dissolved in a mixture of 1,2-Dichloroethane (70 mL, 10 vol) and DMF (70 mL, 10 vol) under nitrogen atmosphere. To this was added acetic acid (4.8 mL, 0.0807 mol, 3.0 equiv) at room temperature. The resulted reaction mixture was stirred for 2 hours at room temperature. At this stage, NaCNBH3(6.6 g, 0.1076 mol, 4 equiv) was added in portions at 0°C and stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 8: 2 / EtOAc: pet ether, Rf~ 0.6, and LCMS), the reaction mixture was diluted with DCM (200 mL) and washed water (3 × 200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated. The resulted product was triturated with hexane (50 mL), filtered and dried under suction to afford tert-Butyl(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 4 (8 g, 69%) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 7.28 (t, J = 7.60 Hz, 1H), 6.93 (d, J = 7.20 Hz, 1H), 6.82 (t, J = 5.60 Hz, 1H), 6.75 (d, J = 8.00 Hz, 1H), 5.58 (t, J = 5.60 Hz, 1H), 5.10-5.14(m, 1H), 4.10-4.25 (m, 2H), 3.11-3.14 (m, 2H), 2.90-2.98 (m, 3H), 2.60-2.64 (m, 1H), 2.28-2.32 (m, 1H), 2.04-2.06 (m, 1H), 1.46-1.58 (m, 4H), 1.37 (s, 9H). LC-MS: 429.2 (M-H), Rt (min): 2.552, Area% - 97.64.

[0169] Step-3: 3-(4-((4-Aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To an ice cold suspension of tert-Butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 4 (800 mg, 1.86 mmol, 1 equiv) in DCM (10 mL) was added HCl in EtOAc (1 M, 8 mL) and stirred for 4 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated and lyophilized to obtain 3-(4-((4- Aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (530 mg, 79%) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.07 (s, 3H), 7.34 (t, J = 7.60 Hz, 1H), 7.05 (d, J = 7.60 Hz, 1H), 6.92 (d, J = 8.00 Hz, 1H), 5.10-5.15 (m, 1H), 4.19-4.37 (m, 2H), 3.19-3.20 (m, 2H), 2.90-2.95 (m, 1H), 2.80-2.89 (m, 2H), 2.51-2.52 (m, 1H), 2.29-2.33 (m, 1H), 2.03-2.06 (m, 1H), 1.66-1.67 (m, 4H).13C-NMR (100 MHz, DMSO-d6): δ 173.34, 171.52, 168.67, 140.34, 133.14, 129.87, 117.06, 114.76, 52.08, 46.58, 44.46, 31.65, 24.90, 23.23. LCMS: 331.3 (M+H). Method: Mobile Phase A: 0.1% Formic Acid in H2O. Mobile Phase B: Acetonitrile. Flow rate: 1.5 mL / min. COLUMN: Atlantis dC18 (50 × 4.6) mm, 5 µ. Rt (min): 1.638; Area% - 99.32. HPLC Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 1.0 mL / min. COLUMN: Atlantis dC18 (250 × 4.6) mm, 5 µm. Rt (min): 7.403; Area% - 98.88.

[0170] Hydrochloride Salt Form of Compound 2

[0171] 3-(4-((4-Aminobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0172] Step-1: tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(methyl)amino)butyl)carbamate Tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 4 (2 g, 4.65 mmol, 1 equiv) and paraformaldehyde (1.39 g, 46.5 mmol, 10 equiv) were taken together in a mixture of 1,2-Dichloroethane (20 mL, 10 vol) and DMF (10 mL, 5 vol) under nitrogen atmosphere. To this, acetic acid (0.8 mL, 13.95 mmol, 3 equiv) was added and the reaction mixture was stirred for 1 hour at room temperature. NaCNBH3(1.15 g, 18.6 mmol, 4 equiv) was added then in portions and the reaction mixture was stirred for additional 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf ~ 0.4, and LCMS), the reaction mixture was diluted with DCM (100 mL) and washed water (3 × 50 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The resulted residue was purified by chromatography (column size: Biotage R snap cartridge, KP-Sil, 50 g, 230-400 silica gel) using 40-45% ethyl acetate in dichloromethane to obtain tert-Butyl(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(methyl)amino)butyl)carbamate (800 mg, 39%) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.15 (d, J = 7.20 Hz, 1H), 6.99 (d, J = 8.00 Hz, 1H), 6.80 (t, J = 5.60 Hz, 1H), 5.08-5.13 (m, 1H), 4.33-4.51 (m,2H), 2.90-2.96 (m, 3H), 2.88 (s, 3H), 2.52-2.62 (m, 2H), 2.01-2.03 (m, 1H), 1.42-1.48 (m, 4H), 1.40 (s, 9H). LC-MS: 445.4 (M-H), Rt (min): 2.525, Area% - 99.11.

[0173] Step 2: 3-(4-((4-Aminobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride To an ice cold solution of tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(methyl)amino)butyl)carbamate 5 (800 mg, 1.80 mmol) in DCM (10 mL), was added HCl in EtOAc (1 M, 8 mL) and stirred for 4 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated and lyophilized to afford 3-(4-((4- Aminobutyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (550 mg, 88%) pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.99 (brs, 3H), 7.37-7.51 (m, 3H), 5.10-5.15 (m, 1H), 4.44-4.63 (m, 2H), 3.30 (s, 2H), 3.01 (s, 3H), 2.92-2.98 (m, 2H), 2.60-2.78 (m, 3H), 2.45-2.50 (m, 1H), 2.06-2.08 (m, 1H), 1.66-1.67 (m, 4H).13C-NMR (100 MHz, DMSO-d6): δ 173.34, 171.30, 167.67, 134.36, 133.03, 130.23, 117.06, 122.84, 55.43, 52.21, 48.02, 42.50, 31.65, 23.02, 22.96. LCMS: 345.1 (M+H). Method: Mobile Phase A: 0.1% Formic Acid in H2O. Mobile Phase B: Acetonitrile. Flow rate: 1.5 mL / min. COLUMN: Atlantis dC18 (50 × 4.6) mm, 5 µ. Rt (min): 1.252; Area% - 98.76. HPLC Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 1.0 mL / min. COLUMN: Atlantis dC18 (250 × 4.6) mm, 5 µm. Rt (min): 6.313; Area% - 97.81.

[0174] Hydrochloride Salt Form of Compound 3

[0175] 3-(4-((4-Aminobutyl)(isopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride

[0176] Step-1: tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(isopropyl)amino)butyl)carbamate tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 4 (1.5 g, 3.4 mmol, 1 equiv) and 2-methoxypropene (1.25 g, 17.5 mmol, 5 equiv) were taken together in 1,2-Dichloroethane (30 mL, 20 vol) and the suspension was cooled to 0°C. To this was added triflouroacetic acid (0.22 mL, 3.0 mmol, 0.9 equiv) in drops. Then sodium triacetoxyborohydride (1.07 g, 5.1 mmol, 1.5 equiv) was added in portions at 0°C under nitrogen atmosphere and the resulted reaction mixture was stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.5, and LCMS), the reaction mixture was diluted with DCM (100 mL) and washed with water (2 × 100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by chromatography (column size: Biotage R snap cartridge, KP-Sil, 50 g, 230-400 silica gel) using 40-45% Ethylacetate in dichloromethane to afford tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(isopropyl)amino)butyl)carbamate (620 mg, 38 %) as white solid. LCMS: 473.4 (M+H). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.454; Area% - 97.90.

[0177] Step 2: 3-(4-((4-Aminobutyl(isopropyl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione hydrochloride To an ice cold solution of tert-Butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(isopropyl)amino)butyl)carbamate 6 (620 mg, 1.313 mmol) in DCM (4 mL) was added HCl in EtOAc (1 M, 4 mL) and stirred for 12 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum and further lyophilized to give the desired compound 3-(4-((4-Aminobutyl(isopropyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (440 mg, 96 %) as pale brown solid.1H-NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 7.98 (s, 3H), 7.72 (s, 2H), 5.12-5.08 (m, 1H), 4.56 (dd, J = 18.00, 56.40 Hz, 2H), 3.82-3.51 (m, 1H), 3.47 (s, 2H), 2.90-2.70 (m, 1H), 2.68-2.65 (m, 3H), 2.44-2.41 (m, 1H), 2.09 (d, J = 5.20 Hz, 1H), 1.53 (t, J = 7.60 Hz, 2H), 1.33 (d, J = 6.80 Hz, 2H), 1.23 (s, 6H).13C-NMR (100 MHz, DMSO-d6): 173.37, 171.25, 167.38, 136.43, 134.63, 130.36, 126.85, 123.25, 60.12, 52.33, 49.80, 48.17, 40.49, 39.24, 38.53, 31.55, 24.53, 22.91, 18.92, 18.62. LCMS: 373.2 (M-HCl). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.239; Area% - 97.330. HPLC: 97.905 %, Rt (min): 6.141.

[0178] Hydrochloride Salt Form of Compound 4

[0179] 3-(4-((4-Aminobutyl)(propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0180] Step-1: tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(propyl)amino)butyl)carbamate tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 4 (1.5 g, 3.4 mmol, 1 equiv) and propionaldehyde (2.0 g, 3.4 mmol, 10 equiv) were dissolved in a mixture of 1,2-Dichloroethane (20 mL) and DMF (10 mL) under nitrogen atmosphere. To this was added acetic acid (0.58 mL, 10.2 mmol, 3 equiv) and the resulted reaction mixture was stirred for 1 hour at room temperature. At this point, sodium cyanoborohydride (0.84 g, 1.3 mmol, 4 equiv) was added in portions and stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.4, and LCMS), the reaction mixture was diluted with DCM (100 mL) and washed water (3 × 100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The resulted residue was purified by chromatography (Isolera, column size: Biotage R snap cartridge, KP-Sil, 50 g, 230-400 silica gel) using 40-45% EtOAc in DCM to obtain tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(propyl)amino)butyl)carbamate 7 (600 mg, 37%) as white solid. LCMS: 473.4 (M+H). Method: Column: Atlantis dC18 (50×4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.709; Area% - 99.720.

[0181] Step 2: 3-(4-((4-Aminobutyl)(propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride To an ice cold solution of tert-Butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(propyl)aminuteso)butyl)carbamate 7 (600 mg, 1.2695 mmol, 1 equiv) in DCM (10 mL) was added HCl in EtOAc (1M, 5 mL) and stirred for 4 hours at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated and further lyophilized to afford 3-(4-((4-Aminobutyl)(propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochloride (360 mg, 68 %) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.99 (s, 3H), 7.53 (s, 2H), 5.12 (q, J = 4.80 Hz, 1H), 4.49 (d, J = 36.40 Hz, 2H), 3.29 (s, 1H), 2.97 (s, 1H), 2.96-2.88 (m, 1H), 2.72 (q, J = 22.80 Hz, 2H), 2.62 (d, J = 16.40 Hz, 1H), 2.44 (s, 1H), 2.06 (t, J = 5.20 Hz, 1H), 2.05 (s, 1H), 1.55 (s, 6H), 0.84 (t, J = 7.20 Hz, 3H).13C-NMR (100 MHz, DMSO-d6): δ 173.34, 171.27, 167.49,162.82, 134.55, 130.45, 125.14, 57.35, 55.02, 52.34, 48.12, 38.58, 36.28, 31.59, 31.26, 24.51, 22.94, 21.57, 19.04, 11.25. LCMS: 373.1 (M-HCl). Method: Column: Atlantis dC18 (50×4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.386; Area% - 98.551. HPLC: 98.878 %, Rt (min): 6.95.

[0182] Hydrochloride Salt Form of Compound 6

[0183] 3-(4-((2-(1-(Aminomethyl)cyclohexyl)ethyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0184] Step-1: 2-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid To a solution of 2-(1-(Aminomethyl)cyclohexyl)acetic acid 1 (30 g, 175.4 mmol, 1 equiv) in THF (300 mL, 10 vol) were added a solution of NaOH (7.0 g, 175.4 mmol, 1 equiv) in water (100 mL, 5 vol) and boc-anhydride (38.2 g, 175.4 mmol, 1 equiv) in drops at 0°C. The mixture was stirred at room temperature for 16 hours. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc in pet ether, Rf~ 0.4, and LCMS-ELSD), the solvent was evaporated to dryness and diluted with water (100 mL) and washed with ethyl acetate (1 × 150 mL). The aqueous layer was separated and acidified with 1.5N HCl to pH 5 to 6 and extracted with DCM (2 × 500 mL). The organic layer was washed with brine (250 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford 2-(1-(((tert- Butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid 2 (35 g, 75%) as white solid.LCMS (ELSD): 270.3 (M-H). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.950; Area% - 99.502.

[0185] Step 2: Methyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetate To a solution of 2-(1-(((tert-Butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid 2 (20 g, 73.8 mmol, 1 equiv) in DMF (200 mL, 10 vol) were added potassium carbonate (20.3 g, 147.6 mmol, 2 equiv) and methyl Iodide (26 mL, 369 mmol, 5 equiv) in drops at 0°C. The mixture was stirred at room temperature for 16 hours. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc in pet ether, Rf~ 0.6, and LCMS-ELSD), the reaction mixture was diluted with ethyl acetate (200 mL) and washed with ice cold H2O (3 × 500 mL). The organic layer was washed with brine (1 × 500 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford Methyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetate 3 (15 g, 71%) as a pale yellow liquid. LCMS (ELSD): 230.3 (M-tert-Butyl). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 3.374; Area% - 99.76.

[0186] Step-3: tert-Butyl 3-hydroxy-2-azaspiro[4.5]decane-2-carboxylate To a solution of Methyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetate 3 (8 g, 28.07 mmol, 1 equiv) in DCM (150 mL) was added DIBAL-H (1 M in hexane, 28.07 mL, 28.07 mmol, 1 equiv) in drops at -78°C. The mixture was stirred at 0°C for 2 hours. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc in pet ether, Rf~ 0.5, and LCMS-ELSD), the reaction mixture was quenched with saturated NH4Cl solution (50 mL) and was filtered through a celite bed and washed with DCM (250 mL). The separatedorganic layer was washed with brine (250 mL), dried over Na2SO4, filtered and concentrated under vacuum below 35°C to afford tert-Butyl 3-hydroxy-2-azaspiro[4.5]decane-2-carboxylate 4 (6 g, crude) as pale brown liquid which was used without purification. LCMS (ELSD): 202.1 (M-tert-Butyl). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.187; Area% - 99.976.

[0187] Step-4: tert-Butyl((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)ethyl)cyclohexyl)methyl)carbamate To a stirred solution of Lenalidomide (CAS # 191732-72-6, 2 g, 7.6 mmol, 1equiv) and tert- Butyl 3-hydroxy-2-azaspiro[4.5]decane-2-carboxylate 4 (5.79 g, 2.3 mmol) in mixture of 1,2- Dichloroethane (20 mL) and DMF (20 mL) was added acetic acid (1.82 mL, 30.7 mmol, 4 equiv) under nitrogen atmosphere. The resulted reaction mixture was stirred for 1 hour at room temperature. Then the reaction mixture was cooled to 0°C and sodium cyanoborohydride (1.84 g, 30.7 mmol, 4 equiv) was added portion-wise and stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc, Rf~ 0.6, and LCMS), the reaction mixture was diluted with DCM (100 mL) and washed water (3 × 50 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The resulted residue was purified by chromatography (column size: Biotage R snap cartridge, KP-Sil, 25 g, 230-400 silica gel) using 40-45% EtOAc in DCM to afford tert-Butyl((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 4-yl)amino)ethyl)cyclohexyl)methyl)carbamate 5 (620 mg, 16%) as white solid. LCMS: 443.4 (M-t- Bu). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 3.072; Area% - 98.042.

[0188] Step-5: 3-(4-((2-(1-(Aminomethyl)cyclohexyl)ethyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride To an ice cold solution of tert-Butyl((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)ethyl)cyclohexyl)methyl)carbamate 5 (620 mg, 1.2437 mmol, 1 equiv) in DCM (10 mL) was added HCl in EtOAc (1 M, 6 mL) and stirred for 12 hours at room temperature. After confirming the completion of reaction by LCMS, the reaction mixture was concentrated under vacuum to give the crude which was co-distilled with Milli-Q H2O (2 × 10 mL) and dried under vacuum to afford 3-(4-((2-(1-(Aminomethyl)cyclohexyl)ethyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (480 mg, 98 %) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 8.05 (s, 3H), 7.43-7.31 (m, 1H), 7.10 (d, J = 7.20 Hz, 1H), 7.01 (d, J = 7.60 Hz, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.39 (d, J = 17.20 Hz, 1H), 4.24 (d, J = 17.60 Hz, 1H), 3.18-2.97 (m, 2H), 2.94-2.89 (m, 1H), 2.79 (d, J = 5.60 Hz, 2H), 2.63 (d, J = 17.20 Hz, 1H), 2.31 (q, J = 4.40 Hz, 1H), 2.06-2.04 (m, 1H), 1.77 (t, J = 7.20 Hz, 2H), 1.44 (s, 10H).13C-NMR (100 MHz, DMSO-d6): δ 173.32, 171.43, 168.37, 138.77, 133.32, 131.39, 129.94, 119.19, 116.76, 52.15, 46.70, 45.18, 41.16, 40.56, 34.88, 33.03, 31.64, 31.49, 25.84, 23.21, 21.11. LCMS: 399.1 (M-HCl). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.551; Area% - 99.47. HPLC: 99.499 %, Rt (min): 8.979.

[0189] Hydrochloride Salt Form of Compound 46

[0190] General Procedure for the Preparation of Compound 6b To a solution of compound 4 (1.0 g, 2.32 mmol, 1 eq.) and compound 5b (336 mg, 4.65 mmol, 2.0 eq.) in DCE / DMF (10 ml) was added acetic acid (1.0 ml), molecular sieve (1.0 g) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (585 mg, 9.3 mmol, 4 eq.) was added in portions and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated and purified by silica gel column chromatography (DCM / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6b (400 mg, 35%) as a white solid. TLC: EA = 100% Rf (Compound 4) = 0.5 Rf(Compound 6b) = 0.6LC-MS: 487.3 [M+1]+

[0191] General Procedure for the Preparation of Compound 46 To a solution of compound 6b (400 mg, 0.873 mmol, 1 eq.) in methanol (1 ml) was added HCl / EA (2N, 8.73 mmol, 10 eq.). The resulting solution was stirred at room temperature for 24 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by P-HPLC (acetonitrile / H2O: 30%-40%) to afford compound 46 (60 mg, 16%) as a white solid. TLC: DCM / methanol = 10 / 1 Rf(Compound 6b) = 0.6 Rf (Compound 46) = 0.2 LC-MS: 387.25 [M+1]+1H NMR (400 MHz, D2O) δ 7.84 (s, 1H), 7.70 (s, 2H), 5.07 (d, J = 8.7 Hz, 1H), 4.55 (s, 3H), 3.51 (s, 4H), 3.18 (s, 1H), 2.73 (d, J = 7.9 Hz, 4H), 2.41 (d, J = 7.5 Hz, 1H), 2.16 (s, 1H), 1.31 (dd, J = 93.7, 45.1 Hz, 8H), 0.65 (s, 3H).

[0192] Hydrochloride Salt Form of Compound 47

[0193] 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0194] Step-3: tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(methyl)amino)butyl)carbamate To a solution of tert-Butyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl) carbamate 4 (3 g, 6.97 mmol, 1 equiv) and pentanal (6.0 g, 69.7 mmol, 10 equiv) in a mixture of 1,2-dichloroethane (60 mL, 20 vol) and DMF (30 mL, 10 vol) was added acetic acid (1.2 mL, 20.91 mmol, 3 equiv) and the reaction mixture was stirred for 2 hour at room temperature. NaCNBH3(1.75 g, 27.9 mmol, 4 equiv) was added in portions and the reaction mixture was stirred for additional 16 h at room temperature. TLC analysis (70% EtOAc in pet-ether) indicated product formation and the starting material was not consumed completely. Additional quantities of pentanal (2 x 6.0 g, 69.7 mmol, 10 equiv), acetic acid (2 x 0.8 mL, 13.94 mmol, 2 equiv) and NaCNBH3(0.87 g, 13.94 mmol, 2 equiv) were added and the resulted reaction mixture was stirred for 36 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 70% EtOAc in pet ether, Rf ~ 0.6, and LCMS), the reaction mixture was diluted with DCM (100 mL), washed with water (3 × 100 mL), brine (300 mL), dried over anhy. Na2SO4, filtered and concentrated. The resulted residue was purified by chromatography (Biotage R snap cartridge, KP-Sil, 100 g, 230-400 silica gel) with 65-70 % ethyl acetate in Pet-ether to get tert- butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)butyl)carbamate 5 (2.5 g, 97%) as white solid.1H-NMR (400 MHz, DMSO-d6): δ (s, 1H), 7.37 (t, J = 8.00 Hz, 1H), 7.18 (d, J = 7.20 Hz, 1H), 7.07 (d, J = 8.00 Hz, 1H), 6.78 (t, J = 5.60 Hz, 1H), 5.11 (q, J = 5.20 Hz, 1H), 4.42-4.27 (m, 2H), 3.17 (t, J = 8.40 Hz, 4H), 2.96-2.90 (m, 3H), 2.68-2.61 (m, 2H), 2.03-2.00 (m, 1H), 1.43 (s, 15H), 1.38 (t, J = 10.80 Hz, 4H), 0.86 (s, 3H). LC-MS: 501.3 (M+H), Rt (min): 1.853, Area% - 97.842.

[0195] Step 4: 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione hydrochlorideTo an ice cold solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)butyl)carbamate (2.5 g, 4.99 mmol) in DCM (25 mL), was added HCl (4M soln. in EtOAc, 12.5 mL) and stirred for 2 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf ~ 0.4), the reaction mixture was concentrated and lyophilized to afford 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione Hydrochloride 47 (2.4 g, 98 %) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.92 (s, 4H), 7.39 (s, 2H), 5.15-5.10 (m, 1H), 3.28 (s, 4H), 2.98-2.92 (m, 1H), 2.75 (d, J = 5.20 Hz, 2H), 2.68-2.64 (m, 2H), 2.08-2.04 (m, 1H), 1.54 (s, 6H), 1.26 (d, J = 13.60 Hz, 5H), 0.87-0.81 (m, 3H). LCMS: 401.2 (M+H). Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: 0.1 % TFA in ACN. Flow rate:1.5 mL / min. Column: XBridge C8 (50 × 4.6 mm) 3.5 μm. Rt (min): 1.356; Area%: 96.152. HPLC: Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 2.0 mL / min. Column: X-Bridge C8(50 ×4.6) mm, 3.5 μm. Rt (min): 2.341; Area%: 99.332.

[0196] Hydrochloride Salt Form of Compound 48

[0197] General Procedure for the Preparation of Compound 6dTo a solution of compound 4 (2.0 g, 4.65 mmol, 1 eq.) and compound 5d (932 mg, 9.30 mmol, 2.0 eq.) in DCE / DMF (20 ml) was added acetic acid (2.0 ml), molecular sieve (1.0 g) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (1.17 g, 18.6 mmol, 4 eq.) was added in portions and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 30 mL) and brine (30 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6 (660 mg, 28%) as a white solid. TLC: EA = 100% Rf(Compound 4) = 0.5 Rf (Compound 6d) = 0.6 LC-MS: 515.40 [M+1]+

[0198] General Procedure for the Preparation of Compound 48 To a solution of compound 6d (660 mg, 1.28 mmol, 1 eq.) in DCM (6 mL) was added HCl / EA (2N, 6.42 mmol, 5 eq.). The resulting solution was stirred at 25 °C for 2 h. The resulting mixturewas concentrated under reduced pressure. The residue was purified by P-HPLC (acetonitrile / H2O: 30%-40%) to afford compound 48 (150.55 mg, 28%) as a white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 6d) = 0.6 Rf(Compound 48) = 0.2 LC-MS: 415.40 [M+1]+1H NMR (400 MHz, CDCl3): δ 10.25 (s, 1H), 7.75 (s, 3H), 7.40 – 7.28 (m, 2H), 6.98 (s, 1H), 5.17 (d, J = 8.9 Hz, 1H), 4.40 (dd, J = 58.4, 16.5 Hz, 2H), 3.13 – 2.54 (m, 9H), 2.03 (d, J = 46.6 Hz, 7H), 1.63 (s, 2H), 1.31 (d, J = 63.7 Hz, 13H), 0.85 (s, 3H).

[0199] Hydrochloride Salt Form of Compound 49

[0200] General Procedure for the Preparation of Compound 2e To a solution of Oxalyl chloride (9.5 g, 74.5 mmol, 1.2 eq.) in DCM (50 mL) was added dropwise to a solution of DMSO (10 mL) in DCM (100 mL) at -78ºC over a period of 15minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 1e (10.0 g, 62.1 mmol, 1.0 eq.) in DCM (50 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (18.8 g, 188.2 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, PE / EA=4 / 1, Rf~0.4, KMnO4or Ninhydrin), the reaction mixture was diluted with DCM (50 mL). The mixture was washed with 10% citric acid (500 mL), water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30ºC to afford Compound 2 (11.4 g, crude) as yellow oil which was used without further purification. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (compound 1e) = 0.2 Rf (compound 2e) = 0.4 LC-MS: No found.

[0201] General Procedure for the Preparation of Compound 5 To a solution of compound 3 (0.2 g, 3.9 mmol, 1.0 eq.) and compound 4 (1.0 g, 3.9 mmol, 1.0 eq.) in DCE / DMF (1 / 1, 20 ml) was added acetic acid (0.7 g, 11.6 mmol, 3.0 eq.). The reaction was stirred for 2 h at room temperature. At this stage, NaBH3CN (1.0 g, 15.4 mmol, 4.0 eq.) was added in portions at 0ºC and stirred for 18 h at room temperature. Upon completion of the reaction, the reaction was diluted with DCM (100 mL). The mixture was washed with water (2 × 20 mL) and brine (2 × 20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / methanol: 3:1) to afford compound 5 (0.75 g, 64%) as a white solid. TLC: EA Rf (Compound 3) = 0.4Rf (Compound 5) = 0.5 LC-MS: 302.25 [M+1]+, 300.25 [M-1]-1H NMR (400 MHz, CDCl3): δ 7.10 (d, J = 5.9 Hz, 1H), 6.70 (d, J = 6.8 Hz, 1H), 5.06 (d, J = 10.9 Hz, 1H), 4.19 (d, J = 15.7 Hz, 1H), 4.07 (d, J = 15.7 Hz, 1H), 3.29 (d, J = 24.2 Hz, 1H), 3.07 (s, 2H), 2.75 (s, 2H), 2.25 (s, 1H), 2.09 (s, 1H), 1.57 (d, J = 6.1 Hz, 2H), 0.91 (s, 3H).1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J = 1.8 Hz, 1H), 8.47 – 8.39 (m, 2H), 8.21 (d, J = 7.4 Hz, 1H), and 8.14 (d, J = 8.4 Hz, 1H).

[0202] General Procedure for the Preparation of Compound 6e To a solution of compound 5 (4.6 g, 15.3 mmol, 1.0 eq.) and compound 2e (4.4 g, 27.5 mmol, 1.8 eq.) in DCE / DMF (80 ml, 1 / 1) was added acetic acid (20 ml) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (3.8 g, 61.1 mmol, 4.0 eq.) was added in portions and stirred for 18 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (400 mL). The mixture was washed with water (2 × 40 mL) and brine (2 × 40 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 2:1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6e (0.7 g, 10%) as a white solid. TLC: EA = 100% Rf(Compound 5) = 0.5 Rf (Compound 6e) = 0.6 LC-MS: 445 [M+1]+, 443 [M-1]-1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.42 (d, J = 31.6 Hz, 2H), 7.12 (s, 1H), 5.22 (d, J = 10.3 Hz, 1H), 4.45 (s, 2H), 3.48 (s, 1H), 3.17 (d, J = 51.0 Hz, 5H), 2.97 – 2.75 (m, 2H), 2.21 (s, 1H), 1.67 (s, 2H), 1.42 (d, J = 17.8 Hz, 14H), 0.87 (s, 3H).

[0203] General Procedure for the Preparation of Compound 49 To a solution of compound 6e (0.2 g, 0.4 mmol, 1.0 eq.) in methanol (2 ml) was added HCl / EA (2 mL, 2N, 4.0 mmol, 10.0 eq.). The resulting solution was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 30%-40%) to afford compound 49 (147 mg, 95%) as a white solid. LC-MS: 345.35 [M+1]+1H NMR (400 MHz, D2O): δ 7.42 – 7.30 (m, 2H), 7.24 (d, J = 7.5 Hz, 1H), 5.00 (dd, J = 12.9, 4.4 Hz, 1H), 4.43 (q, J = 17.3 Hz, 2H), 3.41 (d, J = 5.4 Hz, 2H), 3.06 – 2.93 (m, 4H), 2.75 (dd, J = 25.3, 11.4 Hz, 2H), 2.41 (dd, J = 12.7, 4.6 Hz, 1H), 2.17 – 2.07 (m, 1H), 1.28 (dd, J = 14.2, 7.0 Hz, 2H), 0.65 (t, J = 7.1 Hz, 3H).

[0204] Compound 50

[0205] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(propyl)amino)butyl)acetamide

[0206] Step-1: N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(propyl)amino)butyl)acetamideTo a solution of 3-(4-((4-aminobutyl)(propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl Compound 4 (200 mg, 0.489 mmol, 1 equiv) in pyridine (3 ml) at 0 °C was added acetic anhydride (0.231 ml, 2.445 mmol, 5 equiv) and was allowed to stir at room temperature for 12h. Upon completion of reaction (as confirmed by LCMS) the reaction mixture was concentrated under vacuum to give the crude compound, which was purified by reverse-phase column chromatography (Grace column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase) and the pure fractions were lyophilized to give N-(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(propyl)amino)butyl)acetamide (86 mg, 0.207 mmol, 43.0 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.77 (t, J = 5.20 Hz, 1H), 7.38 (t, J = 7.60 Hz, 1H), 7.18 (t, J = 0.40 Hz, 1H), 7.07 (d, J = 7.60 Hz, 1H), 5.10 (q, J = 5.20 Hz, 1H), 4.35 (q, J = 16.80 Hz, 2H), 3.21-3.13 (m, 4H), 3.00 (q, J = 6.40 Hz, 4H), 2.57 (s, 1H), 2.02 (q, J = 5.20 Hz, 1H), 1.76 (s, 3H), 1.48-1.36 (m, 6H), 0.84 (t, J = 7.60 Hz, 3H). LCMS: 415.1 (M+H), Method: Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: ACN, Column: Atlantis dC18 (50×4.6 mm) 5 μm, Flow Rate: 1.5 ml / min Rt (min): 1.622, Area %: 98.693. HPLC: Method: Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Column: X- Bridge C8(50×4.6) mm, 3.5 μm Flow: 2.0 mL / min, Rt (min): 1.789, Area %: 99.953.

[0207] Hydrochloride Salt Form of Compound 51

[0208] General Procedure for the Preparation of Compound 2gTo a solution of compound 1g (5.0 g, 48 mmol, 1 eq.) and tert-Butylchlorodiphenylsilane (13.2 g, 48 mmol, 1.0 eq.) in DMF (50 ml) was added DIEA (18.6 g, 144 mmol, 3.0 eq.) and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis PE / EA=2:1 and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 10 / 1) to afford compound 2g (7.2 g, 44%) as a clear oil. TLC: PE / EA = 2 / 1 KMnO4Rf (Compound 1g) = 0.1 Rf(Compound 2g) = 0.6 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 5.7 Hz, 4H), 7.38 (d, J = 6.8 Hz, 6H), 3.64 (dd, J = 17.5, 4.3 Hz, 4H), 1.63 – 1.50 (m, 5H), 1.43 (d, J = 6.3 Hz, 2H), 1.04 (s, 10H).

[0209] General Procedure for the Preparation of Compound 3gTo a solution of Oxalyl chloride (3.2 g, 25.2 mmol, 1.2 eq.) in DCM (40 mL) was added dropwise to a solution of DMSO (7.5 mL, 1.0 V) in DCM (35 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 2g (7.2 g, 20.9 mmol, 1.0 eq.) in DCM (20 mL) was added dropwise over a period of 15 minutes at -78ºC. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (6.35 g, 62.9 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis,), the reaction mixture was diluted with DCM (50 mL) and washed with 10% citric acid (30 mL), water (50 mL), brine (50 mL) and dried over Na2SO4. The solution was filtered and concentrated under vacumn below 30ºC to afford Compound 3g (7.03 g) as clear oil which was used without further purification. TLC: PE / EA = 2 / 1 Rf(Compound 2g) = 0.6 Rf (Compound 3g) = 0.81H NMR (400 MHz, CDCl3): δ 9.74 (s, 1H), 7.66 (d, J = 7.3 Hz, 4H), 7.48 – 7.33 (m, 6H), 3.67 (t, J = 6.1 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.79 – 1.68 (m, 2H), 1.60 (dd, J = 14.3, 6.6 Hz, 3H), 1.05 (s, 9H).

[0210] General Procedure for the Preparation of Compound 5gTo a solution of compound 4a (2.2 g, 5.1 mmol, 1 eq.) and compound 3g (7.03 g, 20.6 mmol, 4.0 eq.) in DCE / DMF (10 ml) was added acetic acid (2.2 ml), molecular sieve (7.03 g) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (1.6 g, 25.6 mmol, 5 eq.) was added in portions and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 5g (1.03 g, 27%) as a white solid. TLC: EA = 100% Rf (Compound 4a) = 0.5 Rf(Compound 5g) = 0.7 LC-MS: 755.60 [M+1]+

[0211] General Procedure for the Preparation of Compound 6g To a solution of compound 5g (1.03 g, 1.37 mmol, 1 eq.) in THF was added TBAF / THF (13.7 mL, 1 N, 13.7 mmol, 10 eq.) and stirred for 4 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6g (580 mg, 82%) as a white solid. TLC: EA = 100% Rf(Compound 5g) = 0.7 Rf (Compound 6g) = 0.4LC-MS: 517.30 [M+1]+

[0212] General Procedure for the Preparation of Compound 51 To a solution of compound 6g (200 mg, 0.387 mmol, 1 eq.) in methanol (1.0 ml) was added HCl (2.0 mL, 2N, 4.0 mmol, 10.0 eq.). The resulting solution was stirred at room temperature for 24 h. The reaction was lyophilized to afford compound 51 (164.3 mg, 87%) as a white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 6g) = 0.4 Rf(Compound 51) = 0.2 LC-MS: 417.40 [M+1]+1H NMR (400 MHz, D2O): δ 7.88 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 5.10 – 5.01 (m, 1H), 4.53 (t, J = 13.1 Hz, 3H), 3.56 (d, J = 6.9 Hz, 4H), 3.32 (t, J = 5.7 Hz, 2H), 2.76 (dd, J = 27.9, 6.5 Hz, 4H), 2.47 – 2.32 (m, 1H), 2.16 (s, 1H), 1.54 – 1.07 (m, 11H).

[0213] Hydrochloride Salt Form of Compound 52

[0214] General Procedure for the Preparation of Compound 2h To a solution of Compound 1h (0.5 g, 3.47 mmol, 1.0 eq.) in THF (5 mL) was added dropwise to a solution of LiAlH4(145 mg, 3.82 mmol, 1.1 eq.) in THF (5 mL) at 0ºC under nitrogen atmosphere and then stirred for 4 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, PE / EA=2 / 1, Rf~0.6, KMnO4), the reaction mixture was diluted with MTBE (30 mL) and added Na2SO4‧10H2O. The mixture was stirred for 10 min, filtered and concentrated to afford Compound 2h (350 mg, 77%) as clear oil which was used without further purification. TLC: PE / EA = 2:1, KMnO4Rf (compound 1h) = 0.2 Rf (compound 2h) = 0.61H NMR (400 MHz, CDCl3): δ 3.62 (t, J = 5.7 Hz, 2H), 1.59 – 1.44 (m, 3H), 1.28 (d, J = 15.7 Hz, 5H), 1.17 (s, 3H), 0.85 (d, J = 5.6 Hz, 7H).

[0215] General Procedure for the Preparation of Compound 3hTo a solution of compound 2h (600 mg, 4.61 mmol, 1 eq.) in DCM (30 ml) was added PCC (1.99 g, 9.22 mmol, 2.0 eq.) and stirred for 4 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis PE / EA=3:1), the reaction was added silica gel (4.04 g) and stirred for another 10 minutes. The reaction was filtered and concentrated under reduced pressure below 30ºC to afford compound 3h (714 mg) as clear oil which was used without further purification. TLC: PE / EA = 4 / 1 KMnO4Rf(Compound 2h) = 0.4 Rf(Compound 3h) = 0.71H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 2.41 (s, 2H), 1.56 (d, J = 29.1 Hz, 3H), 1.24 (d, J = 50.5 Hz, 5H), 0.85 (s, 6H).

[0216] General Procedure for the Preparation of Compound 5h To a solution of Compound 4a (799 mg, 1.86 mmol, 1 eq.) and compound 3h (714 mg, 5.57 mmol, 3.0 eq.) in DCE / DMF (6 ml) was added acetic acid (1 ml), molecular sieve (1.0 g) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (467 mg, 7.43 mmol, 4 eq.) was added in portions and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 5h (275 mg, 27%) as a white solid. TLC: EA = 100% Rf (Compound 4a) = 0.4Rf (Compound 5h) = 0.6 LC-MS: 543.55 [M+1]+

[0217] General Procedure for the Preparation of Compound 52 To a solution of compound 5h (200 mg, 0.368 mmol, 1.0 eq.) in methanol (1.0 ml) was added HCl (1.8 mL, 2N, 3.7 mmol, 10.0 eq.). The resulting solution was stirred at room temperature for 24 h. The reaction was lyophilized to afford compound 52 (170.7 mg, 89%) as a white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 5h) = 0.6 Rf (Compound 52) = 0.1 LC-MS: 443.45 [M+1]+1H NMR (400 MHz, D2O): δ 7.84 (d, J = 6.9 Hz, 1H), 7.71 (dd, J = 21.3, 7.2 Hz, 2H), 5.04 (d, J = 9.6 Hz, 1H), 4.51 (t, J = 13.0 Hz, 2H), 3.51 (s, 4H), 2.73 (t, J = 14.1 Hz, 4H), 2.39 (d, J = 9.7 Hz, 1H), 2.14 (s, 1H), 1.31 (dd, J = 76.5, 36.4 Hz, 7H), 1.02 (s, 4H), 0.82 (s, 2H), 0.57 (d, J = 5.5 Hz, 6H).

[0218] Hydrochloride Salt Form of Compound 53

[0219] General Procedure for the Preparation of Compound 2i To a solution of Oxalyl chloride (0.9 g, 6.9 mmol, 1.2 eq.) in DCM (5 mL) was added dropwise to a solution of DMSO (1 mL) in DCM (10 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 1i (1.0 g, 5.7 mmol, 1.0 eq.) in DCM (5 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (1.7 g, 17.1 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, PE / EA=4 / 1, Rf~0.4, KMnO4or Ninhydrin), the reaction mixture was diluted with DCM (10 mL). The mixture was washed with 10% citric acid (10 mL), water (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30ºC to afford Compound 2i (0.9 g, crude) as yellow oil which was used without further purification. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (compound 1i) = 0.2 Rf (compound 2i) = 0.4 LC-MS: No found.1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 4.89 (s, 1H), 3.39 (s, 2H), 2.64 (d, J = 35.8 Hz, 2H), 1.40 (s, 10H).

[0220] General Procedure for the Preparation of Compound 6i To a solution of compound 2i (2.3 g, 13.3 mmol, 2.0 eq.) and compound 5 (2.0 g, 6.6 mmol, 1.0 eq.) in DCE / DMF (1 / 1, 40 ml) was added acetic acid (10 ml) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (1.7 g, 26.6 mmol, 4.0 eq.) was added in portions and stirred for 18 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (200 mL). The mixture was washed with water (2 ×20 mL) and brine (2 × 20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / methanol: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6i (0.4 g, 26%) as a white solid. TLC: EA Rf (Compound 2i) = 0.5 Rf(Compound 6i) = 0.6 LC-MS: 459 [M+1]+, 457.30 [M-1]-

[0221] General Procedure for the Preparation of Compound 53To a solution of compound 6i (0.2 g, 0.4 mmol, 1.0 eq.) in DCM / H2O (1 / 1, 2 ml) was added TFA (4 mmol, 10.0 eq.). The resulting solution was stirred at room temperature for 24 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by P-HPLC eluted with acetonitrile / H2O (30% - 40%) to afford compound 53 (105 mg, 65%) as a white solid. LC-MS: 359.30 [M+1]+, 357.20 [M-1]-1H NMR (400 MHz, CD3OD): δ 7.51 – 7.36 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H), 5.14 (dd, J = 12.9, 4.2 Hz, 1H), 4.46 (s, 2H), 3.31 (d, J = 9.3 Hz, 5H), 3.14 (d, J = 6.5 Hz, 2H), 2.92 (dd, J = 19.2, 11.4 Hz, 3H), 2.78 (d, J = 17.2 Hz, 1H), 2.54 (d, J = 9.8 Hz, 1H), 2.19 (d, J = 5.7 Hz, 1H), 1.82 (s, 2H), 1.57 – 1.44 (m, 2H), 0.88 (t, J = 6.8 Hz, 3H).

[0222] Hydrochloride Salt Form of Compound 55

[0223] 3-(4-((4-aminobutyl)(5-aminopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione dihydrochloride

[0224] Step-1: tert-butyl (5-((tert-butyldimethylsilyl)oxy)pentyl)carbamate To a solution of tert-butyl (5-hydroxypentyl)carbamate 1 (1.0 g, 4.92 mmol, 1.0 equiv) in DCM (20 ml) was added imidazole (0.837 g, 12.30 mmol, 2.5 equiv) and TBS-Cl (1.112 g, 7.38 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 2 h . Upon completion of the reaction (as confirmed by TLC, 50% EtOAc / pet ether, Rf~ 0.5, KMnO4). The reaction mixture was quenched with H2O (20 ml) and extracted with DCM (2 × 20 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give crude of tert-butyl (5-((tert- butyldimethylsilyl)oxy)pentyl)carbamate 2 (1.5 g, 4.70 mmol, 96% yield) as yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 6.74 (s, 1H), 3.54-3.56 (m, 2H), 2.88-2.90 (m, 2H), 1.37-1.43 (m, 6H), 1.156 (s, 9H), 0.86 (s, 9H), 0.03 (s, 6H),

[0225] Step-2: tert-butyl (tert-butoxycarbonyl)(5-((tert- butyldimethylsilyl)oxy)pentyl)carbamate To a stirred solution of tert-butyl (5-((tert-butyldimethylsilyl)oxy)pentyl)carbamate 2 (1.5 g, 4.72 mmol, 1.0 equiv) in THF (20 ml)) at 0 °C was added n-BuLi (2.5 M soln. in hexane, 2.267 ml, 5.67 mmol, 1.2 equiv) and the reaction mixture was stirred for 15min at 0 °C. A solution of (Boc)2O (1.316 ml, 5.67 mmol, 1.2 equiv) in THF (5 ml) was added to the reaction mixture at same temperature. The resulting reaction mixture was warmed to room temperature and stirred for 1 hour. Upon completion of the reaction (as confirmed by TLC analysis, 10% EtOAc / pet ether, Rf~ 0.7, KMnO4). The reaction mixture was quenched with water (10 ml) and extracted with DCM (2 × 50 ml). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford crude of tert-butyl(tert-butoxycarbonyl)(5-((tert- butyldimethylsilyl)oxy) pentyl)carbamate 3 (2.0 g, 4.62 mmol, 98% yield) as a pale yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 3.55-3.58 (m, 2H), 3.44-3.48 (m, 2H), 1.25-1.43 (m, 6H), 1.12 (s, 18H), 0.88 (s, 9H), 0.03 (s, 6H)

[0226] Step-3: tert-butyl (tert-butoxycarbonyl)(5-hydroxypentyl)carbamate To a stirred solution of the tert-butyl (tert-butoxycarbonyl)(5-((tert- butyldimethylsilyl)oxy)pentyl)carbamate 3 (1.9 g, 4.55 mmol) in THF (20 ml) at room temperature. The resulting solution was stirred at room temperature for over night. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc / pet ether, Rf~ 0.2, KMnO4). The reaction mixture was quenched with water (10 ml) and extracted with DCM (2 × 50 ml). The combined organic layer was dried over Na2SO4and cocnentrated under reduced pressure to afford the crude as a dark yellow liquid. The crude compound was purified by Isolera chromatography (Biotage R snap cartridge, KP-Sil, 100 g, 100-200 silica gel) using 15-20% EtOAc in pet-ether. The fractions were collected and concentrated under vaccum to afford tert- butyl (tert-butoxycarbonyl)(5-hydroxypentyl)carbamate 4 (1.0 g, 3.27 mmol, 71.9% yield) as a colorless liquid.1H-NMR (400 MHz, DMSO-d6): δ 4.36 (t, J = 4.80 Hz, 1H), 3.40-3.47 (m, 2H), 3.37-3.40 (m, 2H), 1.48-1.50 (m, 2H), 1.44 (s, 18H), 1.40-1.42 (m, 2H), 1.25-1.27 (m, 2H),

[0227] Step-4: tert-butyl (tert-butoxycarbonyl)(5-oxopentyl)carbamate A solution of oxalyl chloride (0.577 ml, 6.59 mmol, 2.0 equiv) and CH2Cl2(20 ml) was added DMSO (0.936 ml, 13.18 mmol, 4.0 equiv) in CH2Cl2 (5 ml) at -78 °C and stirred for 15 minutes at same temperature. To this, a solution of tert-butyl (tert-butoxycarbonyl)(5- hydroxypentyl)carbamate 4 (1.0 g, 3.30 mmol, 1.0 equiv) in CH2Cl2(5 ml) was added at -78 °C. After stirring the reaction mixture for 30 minutes at -78 °C, triethylamine (2.76 ml, 19.78 mmol, 6.0 equiv) was added in drops at -78 °C. Then, the reaction mixture was slowly warmed to 0 °C and stirred for 30 min. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc / pet ether, Rf~ 0.6, KMnO4), the reaction mixture was diluted with DCM (40 mL) and washed with 10% aq citric acid solution (1 x 40 mL), and water (1 x 40 mL), dried over Na2SO4, filtered and concentrated under vacuum (below 30°C) to afford of tert-butyl (tert- butoxycarbonyl)(5-oxopentyl)carbamate 5 (0.95 g, 3.08 mmol, 93% yield) as a pale yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 0.00 (s, 1H), 3.47 (m, 2H), 2.42-2.46 (m, 2H), 1.47-1.50 (m, 4H), 1.42 (s, 18H),

[0228] Step-5: tert-butyl (tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)pentyl)carbamateTo a stirred mixture of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 6 (0.7 g, 1.626 mmol, 1.0 equiv) and tert-butyl (tert- butoxycarbonyl)(5-oxopentyl)carbamate 5 (0.980 g, 3.25 mmol, 2.0 equiv) in CH2Cl2(10 ml) and DMF (10 ml) was added trifluoroacetic acid (0.501 ml, 6.50 mmol, 4.0 equiv) and stirred for 10 min at 0 °C. Sodium triacetoxyborohydride (1.378 g, 6.50 mmol, 4.0 equiv) was added in portions at 0 °C and the resulted colourless cloudy mass was stirred for 16h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc, Rf ~ 0.7), the reaction mixture was quenched with ice cold water (20 ml) and extarcted with dichloromethane (2 × 50 ml). The combined organic layer was dried over anhy. Na2SO4and concentrated under vaccum to afford the crude product as a pale yellow liquid. The crude compound was purified by Isolera chromatography (Biotage R snap cartridge, KP-Sil, 100-200 g, silica gel) using 60-70% of -ethyl acetate in pet-ether to afford tert-butyl(tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino) butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)pentyl)carbamate 7 (0.65 g, 0.891 mmol, 54.8% yield) as a off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 0.00 (s, 1H), 7.35-7.39 (m, 1H), 7.18-7.20 (m, 1H), 7.06- 7.08 (m, 1H), 6.75-6.78 (m, 1H), 5.08-5.13 (m, 1H), 4.27-4.41 (m, 2H), 3.45-3.46 (m, 2H), 2.89- 2.92 (m, 4H), 2.74-2.74 (m, 4H), 2.51-2.52 (m, 2H), 2.50-2.50 (m, 1H), 2.00-2.03 (m, 1H), 1.45- 1.49 (m, 15H), 1.42 (s, 18H), 1.20-1.26 (m, 2H), LCMS: 616.4 (M-Boc). Method: Atlantis dC18 (50×4.6 mm) 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: CAN, Flow Rate: 1.5 ml / min HPLC: Method: Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile, Flow rate:2.0 ml / min. Column: X-Bridge C8(50×4.6) mm, 3.5 μm. RT: 4.972 min, Area :98.095%

[0229] Step-6: 3-(4-((4-aminobutyl)(5-aminopentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione dihydrochlorideTo a stirred solution of tert-butyl(tert-butoxycarbonyl)(5-((4-((tert-butoxycarbonyl)amino) butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentyl) carbamate 7 (0.35 g, 0.489 mmol, 1.0 equiv) in dichloromethane (5 ml) was added HCl (4M soln. in ethylacetate, 10 ml) at 0 °C and then stirred at room temperature for 3 h. The progress of the reaction was monitored by LCMS. Reaction mixture was concentrated under vaccum at below 40 ºC, to afford pale yellow solid. The obtained solid was dissolved in water (10 ml) and washed with MTBE (2 x 10 ml), the water layer was lypholized to afford 3-(4-((4-aminobutyl)(5-aminopentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl (0.2 g, 0.404 mmol, 83% yield) as a pale yellow solid.1H-NMR (400 MHz, CD3OD): δ 8.20 (s, 2H), 7.83 (s, 1H), 5.22-5.27 (m, 1H), 4.84-4.88 (m, 2H), 3.72 (m, 4H), 2.87-2.97 (m, 6H), 2.63-2.66 (m, 1H), 2.27-2.28 (m, 1H), 1.60-1.70 (m, 7H), 1.42- 1.47 (m, 3H). LCMS: 416.3 (M+H). Method: Column: XBridge C8 (50×4.6 mm) 3.5 μm, Mobile phase : A: 0.1% TFA in H2O, Mobile phase: B: 0.1% TFA in Acetonitrile, Flow Rate: 1.5 ml / min. HPLC: Method: Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Methanol, Flow rate: 0.7 ml / min. Column: Atlantis dC18 (250×4.6) mm, 5 μm. RT: 12.223 min, Area: 98.472%.

[0230] Hydrochloride Salt Form of Compound 56

[0231] General Procedure for the Preparation of Compound 2l To a solution of compound 1l (10 g, 85.6 mmol, 1 eq.) and tert-Butylchlorodiphenylsi-lane (23.25 g, 85.6 mmol, 1.0 eq.) in DMF (100 ml) was added DIEA (32.7 g, 254 mmol, 3.0 eq.) and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis PE / EA=2:1 and LCMS), the reaction was diluted with DCM (20 mL) and washed water (3 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 10 / 1) to afford compound 2l (10.27 g, 35%) as a clear oil. TLC: PE / EA = 2 / 1 KMnO4Rf(Compound 1l) = 0.1 Rf(Compound 2l) = 0.61H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 5.6 Hz, 4H), 7.39 (d, J = 6.8 Hz, 6H), 3.72 – 3.56 (m, 4H), 1.58 (t, J = 14.0 Hz, 5H), 1.31 (d, J = 37.5 Hz, 6H), 1.05 (s, 9H).

[0232] General Procedure for the Preparation of Compound 3lTo a solution of Oxalyl chloride (2.14 g, 16.8 mmol, 1.2 eq.) in DCM (20 mL) was added dropwise to a solution of DMSO (5 mL, 1.0 V) in DCM (20 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 2l (5.0 g, 14.02 mmol, 1.0 eq.) in DCM (10 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (4.3 g, 42.1 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis,), the reaction mixture was diluted with DCM (50 mL). The mixture was washed with 10% citric acid (30 mL), water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacumn below 30ºC to afford Compound 3l (4.9 g) as clear oil which was used without further purification. TLC: PE / EA = 2 / 1 Rf(Compound 2l) = 0.6 Rf (Compound 3l) = 0.8

[0233] General Procedure for the Preparation of Compound 5l To a solution of compound 4a (1.5 g, 3.45 mmol, 1 eq.) and compound 3l (4.9 g, 13.8 mmol, 4.0 eq.) in DCE / DMF (15 ml) was added acetic acid (1.5 ml), molecular sieve (5.0 g) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (1.08 g, 17.2 mmol, 5 eq.) was added in portions and stirred for 16 h at room temperature under nitrogen atmosphere. Uponcompletion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 5l (1.03 g, 29%) as a white solid. TLC: EA = 100% Rf (Compound 4a) = 0.5 Rf(Compound 5l) = 0.7 LC-MS: 769.60 [M+1]+

[0234] General Procedure for the Preparation of Compound 6l To a solution of compound 5l (1.03 g, 1.34 mmol, 1 eq.) in THF was added TBAF / THF (13.4 mL,1 N, 13.4 mmol, 10 eq.) and stirred for 4 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6l (620 mg, 87%) as a white solid. TLC: EA = 100% Rf(Compound 5l) = 0.7 Rf(Compound 6l) = 0.4 LC-MS: 531.45 [M+1]+

[0235] General Procedure for the Preparation of Compound 56To a solution of compound 6l (300 mg, 0.566 mmol, 1 eq.) in methanol (1 ml) was added HCl (2.8 mL, 2N, 5.6 mmol, 10 eq.). The resulting solution was stirred at room temperature for 24 h. The reaction was lyophilized to afford compound 56 (231 mg, 81%) as a white solid. TLC: DCM / methanol = 10 / 1 Rf(Compound 15-A) = 0.4 Rf (Compound 56) = 0.2 LC-MS: 431.40 [M+1]+1H NMR (400 MHz, D2O): δ 7.88 (d, J = 7.0 Hz, 1H), 7.74 (dd, J = 22.2, 7.6 Hz, 2H), 5.07 (d, J = 8.9 Hz, 1H), 4.54 (t, J = 13.1 Hz, 2H), 3.55 (d, J = 5.1 Hz, 4H), 3.34 (s, 2H), 2.87 – 2.67 (m, 4H), 2.41 (d, J = 8.3 Hz, 1H), 2.17 (s, 1H), 1.35 (dd, J = 63.6, 23.7 Hz, 9H), 1.10 (s, 4H).

[0236] Hydrochloride Salt Form of Compound 57

[0237] General Procedure for the Preparation of Compound 2m To a solution of 1m (14.3 g, 138.6 mmol, 1.0 eq.) and TEA (42.0 g, 415.8 mmol, 3.0 eq.) in DCM (150 mL) was added dropwise to a solution of (Boc)2O (36.3 g, 166.3 mmol, 1.2 eq.), then DMAP (1.7 g, 13.9 mmol, 0.1 eq.) was added and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (300 mL) and washed with brine (3 × 50 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford Compound 2m (7.1 g, 24%) as colorless oil which was used further. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (compound 1m) = 0.2 Rf(compound 2m) = 0.4 LC-MS: No found.

[0238] General Procedure for the Preparation of Compound 3mTo a solution of Oxalyl chloride (5.4 g, 42.4 mmol, 1.2 eq.) in DCM (35 mL) was added dropwise to a solution of DMSO (7 mL, 1.0 V) in DCM (70 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 2m (7.1 g, 35.3 mmol, 1.0 eq.) in DCM (35 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (10.7 g, 105.9 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, PE / EA=4 / 1, Rf~0.4, KMnO4or Ninhydrin), the reaction mixture was diluted with DCM (70 mL). The mixture was washed with 10% citric acid solution (35 mL), water (35 mL) and brine (35 mL), dried over Na2SO4. The result mixture was filtered and concentrated under vacuum below 30ºC to afford Compound 3m (7.4 g) as yellow oil which was used further without purification. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (compound 2m) = 0.2 Rf(compound 3m) = 0.4 LC-MS: No found.

[0239] General Procedure for the Preparation of Compound 5m To a solution of compound 3m (7.8 g, 41.7 mmol, 1.8 eq.) and compound 4a (6.0 g, 23.1 mmol, 1.0 eq.) in DCE / DMF (1 / 1, 120 ml) was added acetic acid (30 ml). The reaction was stirred for 2h at room temperature. At this stage, NaBH3CN (5.8 g, 92.6 mmol, 4.0 eq.) was added in portions at 0ºC and stirred for 18 h at room temperature. Upon completion of the reaction, the reaction was diluted with DCM (600 mL). The mixture was washed with water (2 × 60 mL) and brine (2 × 60 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 3 / 1) to afford compound 5m (2.0 g, 19%) as a white solid. TLC: EA Rf(Compound 3m) = 0.4 Rf(Compound 5m) = 0.6 LC-MS: 445.35 [M+1]+, 443.30 [M-1]-

[0240] General Procedure for the Preparation of Compound 6m To a solution of compound 5m (2.0 g, 4.5 mmol, 1.0 eq.) and compound 6 (2.6 g, 45 mmol, 10.0 eq.) in DCE / DMF (40 ml, 1 / 1) was added acetic acid (10 mland stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (1.1 g, 18 mmol, 4.0 eq.) was added in portions and stirred for 18 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (200 mL). The mixture was washed with water (2 × 40 mL) and brine (2 × 40 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluted with DCM / EA: 4:1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6m (0.87 g, 39%) as a white solid. TLC: EA = 100% Rf (Compound 5m) = 0.5 Rf(Compound 6m) = 0.65 LC-MS: 487.40 [M+1]+, 485.40 [M-1]-

[0241] General Procedure for the Preparation of Compound 57 To a solution of compound 6m (870 mg, 1.8 mmol, 1.0 eq.) in methanol (4 ml) was added HCl / EA (9 mL, 2 N, 18 mmol, 10.0 eq.). The resulting solution was stirred 30ºC for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by P-HPLC (acetonitrile / H2O: 30%-40%) to afford compound 57 (144 mg, 30%) as a white solid. LC-MS: 387.40 [M+1]+, 385.15 [M-1]-1H NMR (400 MHz, CD3OD): δ 7.59 (s, 3H), 5.18 (d, J = 10.0 Hz, 1H), 4.57 (s, 2H), 3.47 (s, 3H), 3.00 – 2.74 (m, 5H), 2.55 (d, J = 10.6 Hz, 1H), 2.21 (s, 1H), 1.73 – 1.45 (m, 7H), 1.39 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 6.3 Hz, 4H).

[0242] Hydrochloride Salt Form of Compound 58 To a solution of compound 61 (0.2 g, 0.5 mmol, 1.0 eq.) in THF (2 ml) was added HCl / EA (2.4 mL, 2 N, 4.8 mmol, 10.0 eq.) and stirred at 30ºC for 2 days. The resulting mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 30%-40%) to afford compound 58 (102 mg, 52%) as a white solid.LC-MS: 402.30 [M+1]+, 400.20 [M-1]-1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.25 (s, 1H), 6.90 (d, J = 4.0 Hz, 1H), 6.73 (d, J = 4.0 Hz, 1H), 5.57 (s, 1H), 5.59 (d, J = 12.0 Hz, 1H), 4.26-3.85 (m, 2H), 3.05 (s, 2H), 3.85- 3.75 (m, 1H), 2.70-2.50 (m, 1H), 2.31-2.20 (m, 1H), 1.99 (s, 1H), 1.55 (s, 2H), 0.89 (s, 3H).

[0243] Hydrochloride Salt Form of Compound 60

[0244] General Procedure for the Preparation of Compound 2p To a solution of Oxalyl chloride (2.9 g, 22.85 mmol, 1.2 eq.) in DCM (10 mL) was added dropwise to a solution of DMSO (4.2 mL, 1.0 V) in DCM (20 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 1p (4.2 g, 19.32 mmol, 1.0 eq.) in DCM (10 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (5.8 g, 57.98 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of thereaction (as confirmed by TLC analysis, PE / EA=4 / 1, Rf~0.6, KMnO4or Ninhydrin), the reaction mixture was diluted with DCM (50 mL). The mixture was washed with 10% citric acid (30 mL), water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30ºC to afford Compound 2p (4.1 g, crude) as yellow oil which was used without further purification. TLC: PE / EA = 2:1, KMnO4, Ninhydrin Rf (compound 1p) = 0.2 Rf (compound 2p) = 0.6 LC-MS: No found.1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 6.75 (s, 1H), 2.86 (d, J = 5.2 Hz, 2H), 2.38 (s, 2H), 1.56 – 1.42 (m, 2H), 1.34 (s, 11H), 1.20 (d, J = 5.4 Hz, 3H).

[0245] General Procedure for the Preparation of Compound 5p To a solution of compound 4a (2.07 g, 4.81 mmol, 1 eq.) and compound 2p (4.1 g, 19.32 mmol, 4.0 eq.) in DCE / DMF (20 ml) was added acetic acid (2.1 ml), molecular sieve (4.1 g) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (1.51 g, 24.07 mmol, 5 eq.) was added in portions and stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 2 / 1) and P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 5p (1.0 g, 34%) as a white solid. TLC: EA = 100% Rf(Compound 4a) = 0.5Rf (Compound 5p) = 0.6 LC-MS: 630.60 [M+1]+

[0246] General Procedure for the Preparation of Compound 60 To a solution of compound 5p (200 mg, 0.318 mmol, 1 eq.) in methanol (1 ml) was added HCl (1.6 mL, 2N, 3.2 mmol, 10 eq.). The resulting solution was stirred at room temperature for 24 h. The reaction was lyophilized to afford compound 60 (130 mg, 76%) as a white solid. TLC: DCM / methanol = 10 / 1 Rf(Compound 5p) = 0.6 Rf (Compound 60) = 0.1 LC-MS: 430.40 [M+1]+1H NMR (400 MHz, D2O): δ 7.89 (d, J = 7.1 Hz, 1H), 7.80 – 7.67 (m, 2H), 5.13 – 5.01 (m, 1H), 4.53 (t, J = 13.3 Hz, 2H), 3.56 (s, 4H), 2.72 (d, J = 6.9 Hz, 6H), 2.40 (d, J = 7.9 Hz, 1H), 2.16 (s, 1H), 1.38 (t, J = 36.0 Hz, 8H), 1.12 (s, 4H).

[0247] Compound 61

[0248] General Procedure for the Preparation of Compound 2To a solution of 1q (5.0 g, 50 mmol, 1.0 eq.) in MeOH (100 mL) was added concentrated sulfuric acid (0.58 mL) and stirred for 18 h at the 90 ºC. The solution was cooled to 0 ºC, treaed with NaHCO3(464 mg), and stirred for 10 mins. The reaction mixture was filtered and the solvent was removed in vacuum. The residue was diluted with DCM (50 mL), dried over Na2SO4, filtered and concentrated to afford Compound 2q (5.9 g) as colorless oil which was used without further purification. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (compound 1q) = 0.4 Rf (compound 2q) = 0.2 LC-MS: No found.

[0249] General Procedure for the Preparation of Compound 3q To a solution of Oxalyl chloride (7.6 g, 59.9 mmol, 1.2 eq.) in DCM (33 mL) was added dropwise to a solution of DMSO (6.6 mL) in DCM (66 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 2q (6.6 g, 49.9 mmol, 1.0 eq.) in DCM (33 mL) was added dropwise over a period of 15 minutes. After stirring the reaction mixture for 30 minutes at -78ºC, was added TEA (15.2 g, 149.8 mmol, 3.0 eq.) in drops at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, PE / EA=4 / 1, Rf~0.4, KMnO4or Ninhydrin), the reaction mixture was diluted with DCM (10 mL). The mixture was washed with 10% citric acid (10 mL), water (10 mL) andbrine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30ºC to afford Compound 3q (7.45 g, crude) as yellow oil which was used without further purification. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (compound 2q) = 0.2 Rf (compound 3q) = 0.4 LC-MS: No found.1H NMR (400 MHz, CDCl3): δ 3.65 – 3.52 (m, 5H), 2.29 (td, J = 7.2, 3.8 Hz, 2H), 1.88 – 1.75 (m, 2H), 1.53 (ddt, J = 13.4, 7.4, 3.4 Hz, 2H).

[0250] General Procedure for the Preparation of Compound 61 To a solution of compound 3q (2.5 g, 19.4 mmol, 1.8 eq.) and compound 5 (3.2 g, 10.8 mmol, 1.0 eq.) in DCE / DMF (60 ml, 1 / 1) was added acetic acid (15 ml) and stirred for 1 h at room temperature under nitrogen atmosphere. NaBH3CN (2.7 g, 43 mmol, 4.0 eq.) was added in portions and stirred for overnight at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis, 100% EA and LCMS), the reaction was diluted with DCM (400 mL). The mixture was washed with water (2 × 40 mL) and brine (2 × 40 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 2 / 1) and by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 61 (0.4 g, 13%) as a white solid. TLC: EA = 100% Rf(Compound 5) = 0.5 Rf (Compound 61) = 0.6 LC-MS: 416.35 [M+1]+1H NMR (400 MHz, CD3OD): δ 7.36 (dd, J = 25.2, 7.3 Hz, 2H), 7.17 (d, J = 7.8 Hz, 1H), 5.19 – 5.08 (m, 1H), 4.47 (s, 2H), 3.60 (s, 3H), 3.23 – 3.11 (m, 4H), 2.83 (dd, J = 43.9, 15.0 Hz, 2H), 2.57 (d, J = 13.6 Hz, 1H), 2.31 (t, J = 6.6 Hz, 2H), 2.18 (d, J = 12.4 Hz, 1H), 1.55 (dd, J = 34.0, 6.5 Hz, 6H), 0.88 (t, J = 6.9 Hz, 3H).

[0251] Compound 63 To a solution of compound 58 (120 mg, 0.3 mmol, 1.0 eq.) in THF (2 ml) was added HATU (136 mg, 0.4 mmol, 1.2 eq.), DIEA (151 mg, 1.5 mmol, 5.0 eq.). The resulting solution was stirred at room temperature for 18 h. The resulting mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 30%-40%) to afford compound 63 (63.4 mg, 50%) as a white solid. LC-MS: 415.35 [M+1]+, 413.25 [M-1]-1H NMR (400 MHz, CD3OD): δ 7.82 (s, 1H), 7.36 (dd, J = 25.5, 6.7 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 5.13 (d, J = 12.6 Hz, 1H), 4.46 (s, 2H), 3.18 (d, J = 23.8 Hz, 5H), 2.83 (dd, J = 40.3, 16.7 Hz, 2H), 2.65 (s, 3H), 2.56 (d, J = 13.2 Hz, 1H), 2.14 (s, 3H), 1.55 (d, J = 37.7 Hz, 6H), 1.32 (d, J = 26.3 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H).

[0252] Hydrochloride Salt Form of Compound 66

[0253] General Procedure for the Preparation of Compound 2 To a solution of compound 1 (0.5 g, 8.77 mmol, 1.0 eq.) in DCM (10 mL) were added TEA (2.7 g, 26.3 mmol, 3.0 eq.) and 9-Fluorenylmethyl chloroformate (3.4 g, 13.2 mmol, 1.0 eq.). The mixture was stirred for 16 h at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL) and brine (20 mL), dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 10 / 1) to afford compound 2 (0.4 g, 16%) as white solid. TLC: PE / EA = 1 / 1, Ninhydrin Rf (Compound 1) = 0.1Rf (Compound 2) = 0.81H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 6.4 Hz, 2H), 7.59 (d, J = 6.9 Hz, 2H), 7.45-7.39 (m, 2H), 7.39-7.27 (m, 2H), 5.84 (brs, 1H), 5.25-5.05 (m, 2H), 4.82 (s, 1H), 4.45-4.30 (m, 2H), 4.22 (s, 1H), 3.82 (s, 2H).

[0254] General Procedure for the Preparation of Compound 3 To a solution of compound 2 (0.3 g, 1.1 mmol, 1.0 eq.) in DCM (10 mL) were added acrolein (69 mg, 1.2 mmol, 1.1 eq.) and HG2nd(34 mg, 0.05 mmol, 0.05 eq.). The mixture was stirred at 50ºC overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (10 mL). The mixture was washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 4 / 1) to afford compound 3 (0.28 g, 85%) as yellow solid. TLC: PE / EA = 3 / 1 Rf (Compound 2) = 0.4 Rf(Compound 3) = 0.21H NMR (400 MHz, CDCl3): δ 9.56 (d, J = 6.1 Hz, 1H), 7.75 (s, 2H), 7.57 (s, 2H), 7.47-7.25 (m, 4H), 6.77 (d, J = 14.8 Hz, 1H), 6.25-6.10 (m, 1H), 5.03 (s, 1H), 4.47 (s, 2H), 4.21 (s, 1H), 4.07 (s, 2H).

[0255] General Procedure for the Preparation of Compound 5 To a solution of compound 4 (450 mg, 1.7 mmol, 1.0 eq.) and compound 3 (1.1 g, 3.5 mmol, 2.0 eq.) in DCE / DMF (3 / 1, 8 mL) were added acetic acid (1.2 mL), molecular sieve (1.0 g). Themixture was stirred for 1 h at room temperature under nitrogen atmosphere, then NaBH3CN (437 mg, 6.9 mmol, 4.0 eq.) was added in portions. The reaction mixture was stirred at room temperature overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction mixture was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / EA: 2 / 1) to afford compound 5 (157 mg, 19%) as white solid. TLC: EA = 100% Rf(Compound 4) = 0.4 Rf (Compound 5) = 0.5 LCMS: Calcd. for [C32H30N4O5]+:551, Found: 551.

[0256] General Procedure for the Preparation of Compound 6 To a solution of compound 5 (137 mg, 0.25 mmol, 1.0 eq.) in DCE / DMF (3 / 1, 8 ml) were added butyraldehyde (71.8 mg, 1.0 mmol, 4.0 eq.), acetic acid (1.0 mL) and molecular sieve (1.0 g). The mixture was stirred for 1 h at room temperature under nitrogen atmosphere, the NaBH3CN (62.6 mg, 1.0 mmol, 4.0 eq.) was added in portions. The reaction was stirred at room temperature overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction mixture was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 1 / 1) to afford compound 6 (41 mg, 27%) as white solid. TLC: EA = 100% Rf (Compound 5) = 0.5Rf (Compound 6) = 0.6 LCMS: Calcd. for [C36H38N4O5]+:607, Found: 607.

[0257] General Procedure for the Preparation of Compound 66 To a solution of compound 6 (47 mg, 0.1 mmol, 1.0 eq.) in DCM (4.0 mL) were added piperidine (66.7 mg, 0.8 mmol, 8.0 eq.). The mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 20%-40%) to afford compound 66 (4.4 mg, 13%) as white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 6) = 0.8 Rf(Compound 66) = 0.1 LCMS: Calcd. for [C21H28N4O3]+:385, Found: 385.1H NMR (400 MHz, D2O): δ 7.79 (d, J = 6.3 Hz, 1H), 7.75-7.55 (m, 2H), 5.80-5.70 (m, 1H), 5.70-5.55 (m, 1H), 5.07 (d, J = 12.5 Hz, 1H), 4.55-4.42 (m, 2H), 4.20-4.05 (m, 2H), 3.61-3.37 (m, 2H), 3.34 (s, 2H), 2.87-2.68 (m, 1H), 2.50-2.05 (m, 1H), 1.37-1.24 (m, 2H), 1.24-1.05 (m, 2H), 0.67 (s, 3H).

[0258] Hydrochloride Salt Form of Compound 67

[0259] General Procedure for the Preparation of Compound 2To a solution of compound 1 (3.0 g, 34.8 mmol, 1.0 eq.) and tert-butylchlorodiphenylsilane (2.9 g, 10.5 mmol, 0.3 eq.) in THF (60 mL) were added TEA (17.6 g, 174.3 mmol, 5.0 eq.), DMAP (0.4 g, 3.5 mmol, 0.1 eq.). The mixture was stirred for 17 hours at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (50 mL). The mixture was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 10 / 1) to afford compound 2 (3.0 g, 88%) as clear oil. TLC: PE / EA = 5 / 1 Rf (Compound 1) = 0.1 Rf (Compound 2) = 0.31H NMR (400 MHz, CDCl3): δ 7.75-7.65 (m, 4H), 7.50-7.77 (m, 6H), 4.35 (s, 2H), 4.19 (s, 2H), 1.05 (s, 9H).

[0260] General Procedure for the Preparation of Compound 3 To a solution of compound 2 (3.0 g, 9.3 mmol, 1.0 eq.) in DCM (30 mL) were added TEA (2.8 g, 27.8 mmol, 3.0 eq.) and a solution of MsCl (1.59 g, 13.9 mmol, 1.5 eq.) in DCM (35 mL) at 0ºC over a period of 15 minutes under nitrogen atmosphere. The mixture was stirred for 15 minutes at the same temperature. Then the reaction mixture was slowly warmed to room temperature and stirred for 4 hours. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (50 mL) and washed with water (50 mL), brine (50 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA: 10 / 1) to afford compound 3 (2.9 g, 78%) as clear oil. TLC: PE / EA = 2 / 1 Rf (Compound 2) = 0.60 Rf (Compound 3) = 0.63 LCMS: Calcd. for [C21H26O4SSi]+Na: 425, Found: 425.1H NMR (400 MHz, CDCl3): δ 7.75-7.65 (m, 4H), 7.50-7.77 (m, 6H), 4.81 (s, 2H), 4.37 (s, 2H), 3.02 (s, 3H), 1.04 (s, 9H).

[0261] General Procedure for the Preparation of Compound 4The compound 3 (2.9 g, 7.2 mmol, 1 eq.) was dissolved in NH3 / MeOH (29 mL). The mixture was stirred at room temperature for 17 hours. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM / MeOH: 20 / 1) to afford compound 5 (1.9 g, 82%) as white solid. TLC: DCM / EA = 1 / 1 Rf (Compound 3) = 0.9 Rf(Compound 4) = 0.1 LCMS: Calcd. for [C20H25NOSi]+: 324, Found: 324.1H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.75-7.65 (m, 4H), 7.50-7.77 (m, 6H), 4.29 (s, 2H), 3.52 (s, 2H), 1.03 (s, 9H).

[0262] General Procedure for the Preparation of Compound 5 To a solution of compound 4 (2.08 g, 6.4 mmol, 1 eq.) in DCM (20 mL) were added Fmoc-Osu (2.6 g, 7.7 mmol, 1.2 eq.) and TEA (1.94 g, 19.3 mmol, 3.0 eq.). The mixture was stirred for 17 hours at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction mixture was diluted with DCM (20 mL) and washed with water (3 × 20 mL), brine (20 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA: 1 / 1) to afford compound 5 (2.6 g, 74%) as white solid. TLC: DCM / EA = 1 / 1 Rf(Compound 4) = 0.1Rf (Compound 5) = 0.8 LCMS: Calcd. for [C35H35NO3Si]+Na: 568, Found: 568.

[0263] General Procedure for the Preparation of Compound 6 To a solution of compound 5 (2.6 g, 4.8 mmol, 1.0 eq.) in THF (1.0 ml) was added TEA-3HF (7.7 g, 47.7 mmol, 10.0 eq.). The resulting solution was stirred at room temperature overnight. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction was quenched with H2O (20 mL). The reaction mixture was extracted with EA (20 mL × 3). The organic layer was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 3 / 1) to afford compound 6 (1.0 g, 68%) as white solid. TLC: PE / EA = 2 / 1 Rf(Compound 5) = 0.8 Rf(Compound 6) = 0.21H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 4.43 (d, J = 6.8 Hz, 2H), 4.27 (s, 2H), 4.22 (s, 1H), 4.03 (s, 2H).

[0264] General Procedure for the Preparation of Compound 7 To a solution of compound 6 (1.5 g, 4.9 mmol, 1.0 eq.) in DCM (20 mL) were added MnO2(4.24 g, 49.0 mmol, 10.0 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated to afford compound 7 (1.15 m, 77%) as white solid. It was directly used in next step without further purification. TLC: PE / EA = 2 / 1 Rf (Compound 6) = 0.2 Rf (Compound 7) = 0.51H NMR (399 MHz, CDCl3): δ 9.18 (s, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 5.02 (s, 1H), 4.45 (d, J = 6.6 Hz, 2H), 4.27-4.10 (m, 2H).

[0265] General Procedure for the Preparation of Compound 9 To a solution of compound 8 (1.0 g, 3.8 mmol, 1.0 eq.) and compound 7 (1.2 g, 3.8 mmol, 1.0 eq.) in DCE / DMF (6 mL) were added acetic acid (1.5 mL) and molecular sieve (1.76 g). The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. Then NaBH3CN (1.0 g, 15.3 mmol, 4.0 eq.) was added in portions and stirred for another 16 hours at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 9 (1.3 g, 63%) as white solid. TLC: EA = 100% Rf(Compound 8) = 0.4 Rf (Compound 9) = 0.5

[0266] General Procedure for the Preparation of Compound 10To a solution of compound 9 (1.2 g, 2.2 mmol, 1.0 eq.) and butyraldehyde (0.6 g, 8.7 mmol, 4.0 eq.) in DCE / DMF (3 / 1, 4 mL) were added acetic acid (1.5 ml) and molecular sieve (1.8 g). The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. Then NaBH3CN (546 mg, 8.7 mmol, 4.0 eq.) was added in portions and stirred for another 16 hours at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction mixture was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 10 (315 mg, 24%) as white solid. TLC: EA = 100% Rf (Compound 9) = 0.5 Rf(Compound 10) = 0.6 LCMS: Calcd. for [C36H36N4O5]+: 605, Found: 605.

[0267] General Procedure for the Preparation of Compound 11 To a solution of compound 10 (587 mg, 1.0 mmol, 1.0 eq.) in EtOH (5 mL) were added Lindlar catalyst (60 mg, 10%) and quinoline (12.5 mg, 0.1 mmol, 0.1 eq.). The mixture was stirred at room temperature for 30 minutes under N2 / H2(50%). The reaction mixture was filtered, concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 11 (100 mg, 17%) as white solid. TLC: DCM / EA = 1 / 1 Rf (Compound 10) = 0.7 Rf(Compound 11) = 0.72 LCMS: Calcd. for [C36H38N4O5]+: 607, Found: 607.

[0268] General Procedure for the Preparation of Compound 67To a solution of compound 11 (100 mg, 0.17 mmol, 1.0 eq.) in DCM (5.0 mL) were added piperidine (280 mg, 3.3 mmol, 20.0 eq.). The mixture was stirred at room temperature for 17 hours. Then the reaction mixture was concentrated under reduced pressure and purified by P- HPLC (acetonitrile / H2O: 20%-45%) to afford compound 67 (14.2 mg, 19%) as white solid. TLC: DCM / methanol = 10 / 1 Rf(Compound 11) = 0.9 Rf(Compound 67) = 0.1 LCMS: Calcd. for [C21H28N4O3]+: 385, Found: 385.1H NMR (400 MHz, D2O): δ 7.84 (dd, J = 15.1, 7.8 Hz, 2H), 7.69 (t, J = 7.8 Hz, 1H), 5.72-5.62 (m, 1H), 5.62-5.50 (m, 1H), 5.05 (dd, J = 13.3, 5.2 Hz, 1H), 4.51 (q, J = 17.5 Hz, 2H), 4.23 (d, J = 7.4 Hz, 2H), 3.66-3.52 (m, 2H), 3.38-3.21 (m, 2H), 2.85-2.65 (m, 2H), 2.39 (td, J = 12.9, 7.7 Hz, 1H), 2.22-2.05 (m, 1H), 1.35-1.20 (m, 2H), 1.19-1.06 (m, 2H), 0.63 (t, J = 7.3 Hz, 3H).

[0269] Hydrochloride Salt Form of Compound 68

[0270] General Procedure for the Preparation of Compound 2 To a solution of compound 1 (1.0 g, 5.28 mmol, 1.0 eq.) in EA (3 mL) were added HCl / EA (17.6 mL, 3 N, 52.8 mmol, 10.0 eq.) and stirred for 3 hours at room temperature under nitrogen atmosphere. Upon completion of the reaction (confirmed by TLC analysis), the solution was concentrated under vacuum to afford compound 2 (1.2 g, crude) as yellow oil which was directly used without further purification. TLC: PE / EA = 1 / 1 KMnO4Rf(Compound 1) = 0.4 Rf(Compound 2) = 0.1

[0271] General Procedure for the Preparation of Compound 3To a solution of compound 2 (0.3 g, 3.4 mmol, 1.0 eq.) in THF / H2O (3 / 1, 8 mL) were added Fmoc-Osu (1.7 g, 5.1 mmol, 1.5 eq.) and TEA (340 mg, 3.4 mmol, 1.0 eq.). The mixture was stirred at room temperature overnight. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (10 mL). The mixture was washed with water (10 mL), brine (5 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA: 5 / 1) to afford compound 3 (160 mg, 21%) as white solid. TLC: PE / EA = 2 / 1 Rf (Compound 2) = 0.1 Rf(Compound 3) = 0.71H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 8.5, 2H), 4.50-4.4 (m, 2H), 4.25-4.20 (m, 1H), 3.65 (s, 2H), 3.21 (s, 2H), 1.75-1.37 (m, 4H).

[0272] General Procedure for the Preparation of Compound 4 To a solution of oxalyl chloride (200 mg, 1.6 mmol, 1.2 eq.) in DCM (3 mL) were added dropwise a solution of DMSO (0.4 mL, 1.0 V) in DCM (2 mL) at -78ºC over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. The solution of Compound 3 (410 mg, 1.32 mmol, 1.0 eq.) in DCM (3 mL) was added to the previous solution over a period of 15 minutes at -78ºC. After the mixture was stirred for 30 minutes at - 78ºC, TEA (400 mg, 3.96 mmol, 3.0 eq.) was added at -78ºC. Once addition was complete, the reaction mixture was slowly warmed to 0ºC and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (20 mL) and quenched with 10% aq. citric acid solution (10 mL). The result solution was washed with water (20 mL), brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuumbelow 30ºC to afford Compound 4 (640 mg, crude) as yellow oil which was directly used without further purification. TLC: PE / EA = 4:1, KMnO4, Ninhydrin Rf (Compound 3) = 0.4 Rf(Compound 4) = 0.6

[0273] General Procedure for the Preparation of Compound 6 To a solution of compound 5 (410 mg, 1.6 mmol, 1.0 eq.) and compound 4 (979 mg, 3.2 mmol, 2.0 eq.) in DCE / DMF (10 mL) were added acetic acid (1.5 ml), molecular sieve (1.0 g). The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. Then NaBH3CN (398 mg, 6.4 mmol, 4.0 eq.) was added in portions and stirred at room temperature overnight under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis), the reaction mixture was diluted with DCM (20 mL). The mixture was washed with water (3 × 30 mL), brine (30 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 6 (315 mg, 35%) as white solid. TLC: EA = 100% Rf (Compound 5) = 0.4 Rf (Compound 6) = 0.5

[0274] General Procedure for the Preparation of Compound 7To a solution of compound 6 (642 mg, 1.2 mmol, 1.0 eq.) in THF (3.0 mL) were added dropwise a solution of crotonaldehyde (87.6 mg, 1.3 mmol, 1.1 eq.) of H2SO4(3.11 mL, 4 N, 12.4 mmol, 10.7 eq.) at 0ºC. Then NaBH4(26.8 mg, 0.7 mmol, 0.6 eq.) was added at 0ºC and stirred at same temperature for 40 minutes. The reaction mixture was poured into ice water, extracted with DCM (3 × 30 mL). The organic layer was washed with H2O, brine and concentrated under reduced pressure. The residue was purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 7 (120 mg, 17%) as white solid. TLC: EA = 100% Rf(Compound 6) = 0.5 Rf (Compound 7) = 0.6 LCMS: Calcd. for [C36H38N4O5]+: 607, Found: 607.

[0275] General Procedure for the Preparation of Compound 68 To a solution of compound 7 (120 mg, 0.2 mmol, 1.0 eq.) in DCM (4.0 mL) were added piperidine (171 mg, 2.0 mmol, 10.0 eq.). The mixture was stirred at room temperature for 17 hours. After concentrated under vacuum, the residue was purified by P-HPLC (acetonitrile / H2O: 20%-40%) to afford compound 68 (42.5 mg, 46%) as white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 7) = 0.5Rf (Compound 68) = 0.1 LCMS: Calcd. for [C21H28N4O3]+: 385, Found: 385.1H NMR (400 MHz, D2O): δ 7.76 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 5.75-5.55 (m, 1H), 5.16-5.04 (m, 1H), 4.98 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (dd, J = 35.2, 17.5 Hz, 2H), 3.96 (d, J = 7.2 Hz, 2H), 3.62-3.41 (m, 2H), 2.75-2.55 (m, 4H), 2.32 (qd, J = 13.0, 5.1 Hz, 1H), 2.10-2.01 (m, 1H), 1.51-1.24 (m, 7H).

[0276] Hydrochloride Salt Form of Compound 69

[0277] General Procedure for the Preparation of Compound 2 To a solution of compound 1 (620 mg, 8.8 mmol, 1.0 eq.) in DCM (30 mL) were added MnO2(7.7 g, 88.5 mmol, 10.0 eq.), molecular sieve (3.1 g) and stirred for 17 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis), the reactionmixture was filtered and concentrated under reduced pressure below 30ºC to afford compound 2 (110 mg, 17%) as a clear oil which was directly used without further purification. TLC: PE / EA = 3 / 1 KMnO4Rf (Compound 1) = 0.3 Rf(Compound 2) = 0.31H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 2.05 (s, 3H).

[0278] General Procedure for the Preparation of Compound 4 To a solution of compound 3 (2.0 g, 4.6 mmol, 1.0 eq.) and compound 2 (1.62 g, 18.4 mmol, 4.0 eq.) in DCE / DMF (3 / 1, 8 mL) were added acetic acid (2.0 mL), molecular sieve (4.0 g). The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. Then NaBH3CN (1.2 g, 18.4 mmol, 4.0 eq.) was added in portions and stirred overnight at room temperature under nitrogen atmosphere. Upon completion of the reaction (as confirmed by TLC analysis and LCMS), the reaction mixture was diluted with DCM (20 mL). The mixture was washed with water (3 × 20 mL), brine (20 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 4 (110 mg, 5%) as white solid. TLC: EA = 100% Rf (Compound 3) = 0.4 Rf(Compound 4) = 0.5 LCMS: Calcd. for [C26H34N4O5]+: 483, Found: 483.

[0279] General Procedure for the Preparation of Compound 5To a solution of compound 4 (100 mg, 0.2 mmol, 1.0 eq.) in EtOH (5 mL) were added Lindlar catalyst (10 mg, 10%) and quinoline (1.8 mg, 0.02 mmol, 0.1 eq.). The mixture was stirred at room temperature for 30 minutes, filtered and concentrated under reduced pressure. The residue was purified by P-HPLC (acetonitrile / H2O: 40%-60%) to afford compound 5 (20 mg, 20%) as white solid. TLC: DCM / methanol = 1 / 1 Rf(Compound 4) = 0.6 Rf(Compound 5) = 0.62 LCMS: Calcd. for [C26H36N4O5]+: 485, Found: 485.

[0280] General Procedure for the Preparation of Compound 69 To a solution of compound 5 (33 mg, 0.07 mmol, 1.0 eq.) in MeOH (1 mL) were added HCl (0.4 mL, 2 N, 0.8 mmol, 11.0 eq.). The mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was purified by Biotage (C18, acetonitrile / H2O: 30%-60%) to afford compound 69 (17.8 mg, 57%) as white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 5) = 0.5 Rf(Compound 69) = 0.1LCMS: Calcd. for [C21H28N4O3]+: 385, Found: 385.1H NMR (400 MHz, D2O): δ 7.87-7.77 (m, 2H), 7.72-7.61 (m, 1H), 5.80-5.61 (m, 1H), 5.27- 5.12 (m, 1H), 5.04 (d, J = 10.0 Hz, 1H), 4.50 (q, J = 17.4 Hz, 2H), 4.16 (d, J = 6.2 Hz, 2H), 3.70- 3.55 (m, 2H), 2.82-2.61 (m, 4H), 2.48-2.30 (m, 1H), 2.20-2.04 (m, 1H), 1.58-1.31 (m, 4H), 1.22 (d, J = 5.2 Hz, 3H).

[0281] Hydrochloride Salt Form of Compound 80

[0282] 3-(4-((4-(methylamino)butyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.Hydrochloride

[0283] Step-1: tert-butyl methyl(4-oxobutyl)carbamate To a solution of oxalyl chloride (0.25 mL, 2.95 mmol, 1.2 equiv) in DCM (5 mL) was added DMSO (0.419 mL, 5.90 mmol, 2.4 equiv) at -78° C in drops, over a period of 5 min under nitrogen atmosphere and stirred for 15 min at the same temperature. To this, a solution of tert- butyl (4-hydroxybutyl)(methyl)carbamate 1 (500 mg, 5.90 mmol, 1 equiv) in DCM (2.5 mL) was added dropwise over a period of 5 minutes. After stirring the reaction mixture for 30 min at -78°C, triethylamine (1.713 mL, 12.30 mmol, 5 equiv) was added in drops at -78 °C. After the addition, the reaction mixture was slowly warmed to 0 °C and stirred for 30 min. Upon completion of the reaction (as confirmed by TLC analysis, 50% EtOAc / pet ether, Rf~ 0.4, KMnO4), the reaction mixture was diluted with DCM (20 mL) and washed with 10% aq citric acid solution (20 mL), water (1 x 10 mL) and brine (1 x 10 mL), dried over anhy. Na2SO4, filtered and concentrated under vacuum (below 30°C) to afford tert-butyl methyl(4- oxobutyl)carbamate 2 (450 mg, crude) as pale yellow liquid which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 9.67 (s, 1H), 3.16 (t, J = 7.20 Hz, 2H), 2.69 (s, 3H), 2.43- 2.38 (m, 2H), 1.71 (t, J = 6.80 Hz, 2H), 1.41 (s, 3H).

[0284] Step-2: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)(methyl)carbamate A mixture of tert-butyl methyl(4-oxobutyl)carbamate (279 mg, 1.389 mmol, 1.2 equiv) and Lenolidamide 3 (300 mg, 1.157 mmol, 1 equiv) were dissolved in a mixture of 1,2- Dichloroethane (3 mL, 10 vol) and DMF (3 mL, 10 vol) under nitrogen atmosphere. To this solution, TFA (0.08 mL, 1.041 mmol, 0.9 equiv) and Na(OAc)3BH (368 mg, 1.736 mmol, 1.5 equiv) were added in portions at 0 °C and stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100 % EtOAc, Rf~ 0.4, and UPLC), the reaction mixture was diluted with DCM (20 mL), washed with water (3 × 20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by Isolera (Biotage R snap cartridge, KP-Sil, 25 g, 230-400 mesh silca gel) using 80-85% ethyl acetate in pet ether. The pure fractions were collected and concentrated under vacuum to give tert-butyl (4- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)(methyl)carbamate 4 (350 mg, 0.760 mmol, 65% yield) as off white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.29 (t, J = 7.60 Hz, 1H), 6.93 (d, J = 6.80 Hz, 1H), 6.75 (d, J = 8.40 Hz, 1H), 5.61 (s, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.23 (d, 1H), 4.13 (d, J = 17.20 Hz, 1H), 3.21-3.14 (m, 3H), 2.88 (q, 2H), 2.72 (t, 3H), 2.58 (d, 2H), 2.46-2.28 (m, 2H), 1.55 (s, 3H), 1.37 (s, 9H). LCMS:345.1 (M-Boc), Rt (min): 2.267, Area %: 96.498.

[0285] Step-3: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)butyl)(methyl)carbamate A mixture of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)(methyl)carbamate 4 (350 mg, 0.787 mmol, 1 equiv) and pentanal (339 mg, 3.94 mmol, 5 equiv) were dissolved in a mixture of CH2Cl2(3.5 mL, 10 vol) and DMF (3.5 mL, 10 vol) under nitrogen atmosphere. To this TFA (0.05 mL, 0.709 mmol, 0.9 equiv) and STAB (250 mg, 1.181 mmol, 1.5 equiv) were added in portions at 0 °C and stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100 % EtOAc, Rf ~ 0.6, and UPLC), the reaction mixture was diluted with DCM (20 mL), washed water (3 x 20 mL), brine (20 mL), dried over anhy. Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by Isolera (Biotage R snap cartridge, KP-Sil, 25 g, Silica gel 230-400 mesh) using 70-80% ethyl acetate in pet ether. The pure fractions were collected and concentrated under vacuum to give the desired product to afford tert-butyl(4-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)butyl)(methyl)carbamate 5 (130 mg, 0.241 mmol, 30% yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.38 (t, J = 8.00 Hz, 1H), 7.19 (d, J = 7.20 Hz, 1H), 7.08 (d, J = 8.40 Hz, 1H), 5.11 (q, J = 5.20 Hz, 1H), 4.34 (d, 1H), 4.29 (d, 1H), 3.22-3.11 (m, 6H), 2.92-2.87 (m, 2H), 2.70 (q, J = 2.00 Hz, 3H), 2.57 (s, 2H), 2.01 (t, J = 5.20 Hz, 1H), 1.25-1.40 (m, 18H), 0.84 (t, J = 7.20 Hz, 3H). LCMS: 515.4 (M+H), Rt (min): 1.989, Area %: 95.589.

[0286] Step-4: 3-(4-((4-(methylamino)butyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione To an ice cold suspension of tert-Butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate (130 mg, 0.240 mmol, 1 equiv) in DCM (1.5 mL) was added HCl (4M soln. in EtOAc, 0.7 mL) and stirred for 2 h at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated and the residue was triturated with MTBE (10 ml). The solid obtained was lyophilized to get 3-(4-((4- (methylamino)butyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.hydrocholide 80 (70 mg, 63.2%) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.83 (s, 2H), 7.53 (s, 3H), 5.15-5.10 (m, 1H), 4.48-4.49 (m, 2H), 3.31 (s, 4H), 2.97-2.88 (m, 1H), 2.82 (s, 1H), 2.74 (s, 2H), 2.51-2.48 (m, 3H), 1.91 (s, 1H), 1.59 (t, J = 6.40 Hz, 2H), 1.46 (d, J = 17.20 Hz, 3H), 1.24 (s, 4H), 0.82 (t, J = 6.80 Hz, 3H). LCMS: 415.2 (M+H), Method: Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: ACN, Column: Atlantis dC18 (50 × 4.6 mm) 5 μm, Flow Rate: 1.5 ml / min Rt (min): 1.599, Area %: 95.709. HPLC: Method: Mobile phase:A: 0.1% TFA in water, Mobile phase: B: ACN, Column:X- Bridge C8(50 × 4.6) mm, 3.5 μm Flow: 2.0 mL / min, Rt (min): 2.409, Area %: 97.597.

[0287] Formic acid salt Form of Compound 81

[0288] 3-(4-((4-(dimethylamino)butyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione formic acid salt To a solution of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 47 (300 mg, 0.749 mmol) and paraformaldehyde (450 mg, 14.98 mmol, 20 equiv) in DCM (6 mL, 20 vol) was added AcOH (0.129 ml, 2.247 mmol, 3 equiv) and the reaction mixture was stirred for 2 h at room temperature. NaCNBH4(188 mg, 3.00 mmol, 4 equiv) was added to the mixture in portions and the reaction mixture was stirred for additional 40 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, EtOAc, Rf ~ 0.4), the reaction mixture was diluted with DCM (10 mL), washed with water (2 x 20 mL), brine (20 mL), dried over anhy. Na2SO4, filtered and concentrated. The resulted residue was purified by prep.HPLC (HCOOH:ACN method) and lyophilized to get 3-(4-((4-(dimethylamino)butyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 81 (26 mg, 0.059 mmol, 7.90% yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.42-7.38 (m, 1H), 7.22 (t, J = 7.20 Hz, 1H), 7.12 (q, J = 3.20 Hz, 1H), 5.23-5.18 (m, 1H), 5.14-5.05 (m, 1H), 4.40 (d, J = 7.20 Hz, 1H), 4.32 (d, J = 4.40 Hz, 1H), 3.25-3.17 (m, 4H), 2.82-2.68 (m, 3H), 2.53-2.50 (m, 6H), 2.34 (s, 2H), 1.63 (q, J = 3.20 Hz, 2H), 1.44 (d, J = 6.40 Hz, 4H), 1.27-1.23 (m, 4H), 0.85-0.9 (m, 3 H). LCMS: 429.3 (M+H). Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: 0.1% TFA in ACN. Flow rate: 1.5 mL / min. Column: XBridge C8 (50×4.6 mm) 3.5 μm. Rt (min): 1.824; Area%: 97.584. HPLC: Method: Mobile Phase A: 0.1%TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 2.0 mL / min. Column: X-Bridge C8(50X4.6) mm,3.5μm. Rt (min): 3.658; Area%: 97.694.

[0289] Compound 82

[0290] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)butyl)acetamide To a solution of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 47 (200 mg, 0.499 mmol) in pyridine (3 ml) was added acetic anhydride (0.236 ml, 2.497 mmol, 5 equiv) dropwise and the reaction mixture was stirred for 13 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 10% MeOH in DCM, Rf ~ 0.8, and LCMS), the reaction mixture was concentrated under vacuum, diluted with EtOAc (10 mL), washed with water (2 × 20 mL), brine (20 mL), dried over anhy. Na2SO4, filtered and concentrated. The resulted residue was purified by chromatography (Biotage R snap cartridge, KP-Sil, 25 g, 230-400 silica gel) with 3-4 % MeOH in DCM and lyophilised to get N-(4-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)butyl)acetamide 82 (120 mg, 0.267 mmol, 53.5 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.78 (t, J = 5.60 Hz, 1H), 7.38 (t, J = 7.60 Hz, 1H), 7.19 (d, J = 7.20 Hz, 1H), 7.07 (d, J = 8.00 Hz, 1H), 5.10 (t, J = 5.20 Hz, 1H), 4.40 (d, J = 16.80 Hz, 1H), 4.29 (d, J = 16.80 Hz, 1H), 3.17 (t, J = 8.40 Hz, 4H), 2.95 (q, J = 1.60 Hz, 3H), 2.62-2.53 (m, 1H), 2.48 (s, 1H), 2.02 (d, J = 5.20 Hz, 1H), 1.76 (s, 3H), 1.47-1.38 (m, 6H), 1.28- 1.22 (m, 4H), 0.84 (t, J = 6.80 Hz, 3H). LCMS: 443.3 (M+H). Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: 0.1 % TFA in ACN. Flow rate:1.5 ml / min. Column: XBridge C8 (50 × 4.6 mm) 3.5 μm. Rt (min): 1.414; Area%: 98.439. HPLC: Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 2.0 mL / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. Rt (min): 2.445; Area%: 98.636.

[0291] Hydrochloride Salt Form of Compounds 87

[0292] 3-(4-(((1S,4S)-4-aminocyclohexyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0293] Step-1: tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)carbamate 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (0.5 g, 1.547 mmol, 1 equiv), tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate 2 (0.995 g, 4.64 mmol, 3 equiv) and NaOt-Bu (0.446 g, 4.64 mmol, 3 equiv) were dissolved in DMF (2 ml) and de-gassed for 20 min with nitrogen. Pd- PEPPSI-IHept(Cl) (0.075 g, 0.077 mmol, 0.05 equiv) was added under nitrogen atmosphere and heated the reaction at 110 °C for 4 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.4, and LCMS), the reaction mixture was filtered through Celite bed, washed with THF (10 mL), concentrated to minimum volume (3 mL) and purified by reverse-phase column chromatography (Grace® column: C1840 µm, 120 g; flow rate: 20mL / min; 0.1% aqueous HCOOH / ACN mobile phase) to obtain tert-butyl ((1S,4S)-4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl)carbamate 3 (110 mg, 0.240 mmol, 15% yield) as pale yellow solid. LCMS: 401.1 (M-Boc). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.110; Area% - 94.51.1H-NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.28 (t, J = 7.60 Hz, 1H), 6.94 (d, J = 6.80 Hz, 1H), 6.79 (d, J = 8.00 Hz, 1H), 6.61 (m, 1H), 5.14 (q, J = 5.20 Hz, 1H), 5.07 (d, J = 6.40 Hz, 1H), 4.22 (q, J = 17.20 Hz, 2H), 3.47-3.42 (m, 2H), 2.98-2.90 (m, 1H), 2.06-2.04 (m, 1H), 1.66 (m, 6H), 1.58-1.54 (m, 4H), 1.39 (s, 9H).

[0294] Step-2: tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)carbamate To a solution of tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)carbamate 3 (110 mg, 0.241 mmol, 1 equiv), pentanal 4 (0.128 ml, 1.205 mmol, 5 equiv) in DCM (4 ml) and DMF (4 ml) at 0 °C was added TFA (0.017 ml, 0.217 mmol, 0.9 equiv ) followed bysodium triacetoxyborohydride (77.0 mg, 0.361 mmol, 1.5 equiv). The reaction mixture was warmed to RT and stirred at same temperature for 16 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.5, and LCMS), the reaction mixture was diluted with ice-cold water (15 mL), extracted with ethyl acetate (2 x 15 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions from the column were lyophilized to afford tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pentyl)amino)cyclohexyl)carbamate 5 (74 mg, 0.140 mmol, 58% yield) as white solid.LCMS: 527.3 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.644; Area% - 99.9.1H-NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.41 (t, J = 7.60 Hz, 1H), 7.26 (q, J = 7.60 Hz, 2H), 6.97 (d, J = 6.40 Hz, 1H), 5.08 (q, J = 5.20 Hz, 1H), 4.31 (q, J = 17.20 Hz, 2H), 3.55 (s, 1H), 3.32-2.91 (m, 3H), 2.96-2.80 (m, 1H), 2.60-2.55 (m, 1H), 2.04-2.00 (m, 1H), 1.82-1.79 (m, 2H), 1.65-1.63 (m, 2H), 1.46-1.40 (m, 12H), 1.27 (m, 6H), 0.81 (t, J = 7.20 Hz, 3H).

[0295] Step-3: 3-(4-(((1S,4S)-4-aminocyclohexyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride To an ice cold solution of tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)carbamate 5 (74 mg, 0.141 mmol, 1 equiv) in DCM (4 mL) was added HCl (4M soln. in EtOAc, 4 mL) and stirred for 1.5 h at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated, washed with MTBE (2 × 5 mL) and further lyophilized to afford 3-(4-(((1S,4S)-4- aminocyclohexyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride 87 (44 mg, 0.093 mmol, 97 % yield) as off white solid. LCMS: 427.2 (M-HCl). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.634; Area% - 85.00. HPLC: 97.53 %, Rt (min): 9.103. Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow: 1.0 mL / min.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 10.98 (s, 3H), 7.45-7.34 (m, 3H), 5.11 (dd, J = 5.20, 13.20 Hz, 1H), 4.41-4.32 (m, 2H), 3.24 (m, 4H), 2.93-2.92 (m, 1H), 2.63-2.50 (m, 2H), 2.02 (t, J = 6.80 Hz, 1H), 1.91-1.68 (m, 4H), 1.65-1.58 (m, 4H), 1.58-1.21 (m, 6H), 0.80 (t, J = 6.80 Hz, 3H).

[0296] Hydrochloride Salt Form of Compound 88

[0297] 3-(4-(((1R,4R)-4-aminocyclohexyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0298] Step-1: tert-butyl ((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)carbamate 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (0.5 g, 1.547 mmol, 1 equiv), tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate 2 (0.995 g, 4.64 mmol, 3 equiv) and NaOt-Bu (0.446 g, 4.64 mmol, 3 equiv) were dissolved in DMF (2 ml) and de-gassed for 20 min with nitrogen. Pd- PEPPSI-IHept(Cl) (0.075 g, 0.077 mmol, 0.05 equiv) was added under nitrogen atmosphere and heated the reaction at 110 °C for 4 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.4, and LCMS), the reaction mixture was filtered through celite, washed with THF (10 mL), concentrated to minimum volume (3 mL) and purified by reverse- phase column chromatography (Grace® column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1%aqueous HCOOH / ACN mobile phase) to obtain tert-butyl ((1R,4S)-4-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl)carbamate 3 (0.040 g, 0.086 mmol, 5% yield) as cream color solid. LCMS: 401.1 (M-Boc). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.188; Area% - 98.18.1H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.27 (t, J = 7.20 Hz, 1H), 6.91 (d, J = 7.20 Hz, 1H), 6.80 (t, J = 8.00 Hz, 2H), 5.29 (d, J = 6.80 Hz, 1H), 5.12 (q, J = 4.80 Hz, 1H), 4.16 (q, J = 17.20 Hz, 2H), 2.93-2.89 (m, 1H), 2.70-2.60 (m, 2H), 2.30-2.20 (m, 2H), 2.09-1.99 (m, 3H), 1.80 (m, 2H), 1.39 (s, 9H), 1.32-1.24 (m, 4H).

[0299] Step-2: tert-butyl ((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)carbamate To a stirred solution of tert-butyl-((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino) cyclohexyl) carbamate 3 (0.040 g, 0.086 mmol, 1 equiv), pentanal (0.076 g, 0.876 mmol, 10 equiv) in DCM (1.5 ml) and DMF (1.5 ml) at 0 °C were added TFA (0.012 ml, 0.158 mmol, 1.8 equiv) and sodium triacetoxyborohydride (56 mg, 0.262 mmol, 3 equiv) and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.5, and LCMS), the reaction mixture was diluted with ice-cold water (15 mL), extracted with ethyl acetate (2 × 15 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions from the column were lyophilized to afford tert-butyl ((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)carbamate 5 (20 mg, 0.038 mmol, 43% yield) as white solid.LCMS: 527.3 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.876; Area% - 99.04.

[0300] Step-3: 3-(4-(((1R,4R)-4-aminocyclohexyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride To an ice cold solution of tert-butyl ((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)carbamate 5 (20 mg, 0.038 mmol, 1 equiv) in DCM (1 mL) was added HCl (4M soln. in EtOAc, 0.5 mL) and stirred for 3 h at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated, washed with MTBE (2 × 5 mL) and lyophilized to afford 3-(4-(((1R,4R)-4-aminocyclohexyl)(pentyl)amino)- 1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride 88 (17 mg, 0.036 mmol, 99 % yield) as off white solid. LCMS: 427.2 (M-HCl). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.579; Area% - 98.76. HPLC: 99.10 %, Rt (min): 2.381. Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow: 2.0 mL / min.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.91 (br s, 3H), 7.44-7.32 (m, 3H), 5.13 (dd, J = 5.20, 13.20 Hz, 1H), 4.35-4.07 (m, 2H), 3.11-2.88 (m, 5H),2.68-2.61 (m, 2H), 2.02-1.95 (m, 3H), 1.78 (s, 2H), 1.60-1.57 (m, 2H), 1.40-1.31 (m, 2H), 1.24-1.20 (m, 6H), 0.81-0.80 (m, 3H).

[0301] Hydrochloride Salt Form of Compound 89

[0302] 3-(4-(((1S,4S)-4-(aminomethyl)cyclohexyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0303] Step-1: tert-butyl (((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)methyl)carbamate 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (1.0 g, 3.09 mmol, 1 equiv), tert-butyl (((1s,4s)-4-aminocyclohexyl)methyl)carbamate 2 (1.060 g, 4.64 mmol, 1.5 equiv) and NaOt-Bu (0.892 g, 9.28 mmol, 3 equiv) were dissolved in DMF (5 ml) and de-gassed for 20 min with nitrogen. Pd-PEPPSI-IHept(Cl) (0.151 g, 0.155 mmol, 0.05 equiv) was added under nitrogen atmosphere and heated the reaction at 110 °C for 4 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.4, and LCMS), the reaction mixture was filtered through Celite bed, washed with THF (10 mL), concentrated to minimum volume (3 mL) and purified by reverse-phase column chromatography (Grace® column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase) to obtain tert-butyl (((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl)methyl)carbamate 3 (140 mg, 0.272 mmol, 8.78 % yield) as pale yellow solid. LCMS: 415.1 (M-Boc). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.325; Area% - 89.09.

[0304] Step-2: tert-butyl (((1s,4s)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)methyl)carbamate To a solution of tert-butyl (((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)methyl)carbamate 3 (80 mg, 0.170 mmol, 1 equiv), pentanal 4 (73.2 mg, 0.850 mmol, 5 equiv) in DCM (2 ml) and DMF (2 ml) at 0 °C was added TFA (0.012 ml, 0.153 mmol, 0.9 equiv ) followed bysodium triacetoxyborohydride (54 mg, 0.255 mmol, 1.5 equiv). The reaction mixture was warmed to RT and stirred at same temperature for 16 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.5, and LCMS), the reaction mixture was diluted with ice-cold water (15 mL), extracted with ethyl acetate (2 x 15 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions from the column were lyophilized to afford tert-butyl (((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)(pentyl)amino)cyclohexyl)methyl)carbamate 5 (35 mg, 0.060 mmol, 35.5% yield) as off white solid. LCMS: 541.3 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.648; Area% - 93.13.

[0305] Step-3: 3-(4-(((1S,4S)-4-(aminomethyl)cyclohexyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochlorideTo an ice cold solution of tert-butyl (((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)methyl)carbamate 5 (35 mg, 0.065 mmol, 1 equiv) in DCM (1 mL) was added HCl (4M soln. in EtOAc, 3 mL) and stirred for 1.5 h at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated, washed with MTBE (2 × 5 mL) and lyophilized to afford 3-(4-(((1S,4S)-4- (aminomethyl)cyclohexyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride 89 (22.5 mg, 0.045 mmol, 69 % yield) as off white solid. LCMS: 441.3 (M-HCl). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% TFA in H2O B: 0.1% TFA in ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.408; Area% - 94.03. HPLC: 94.36 %, Rt (min): 8.083. Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow: 1.0mL / min.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.84 (s, 3H), 7.34 (d, J = 6.40 Hz, 3H), 5.11 (dd, J = 4.80, 12.20 Hz, 1H), 4.38-4.24 (m, 2H), 3.19-3.10 (m, 3H), 2.92-2.84 (m, 3H), 2.69-2.68 (m, 2H), 1.95 (s, 1H), 1.75 (s, 1H), 1.60-1.50 (m, 4H), 1.49-1.30 (m, 4H), 1.24-1.20 (m, 6H), 0.80-0.78 (m, 3H).

[0306] Hydrochloride Salt Form of Compound 90

[0307] 3-(4-(((1R,4R)-4-(aminomethyl)cyclohexyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0308] Step-1: tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)methyl)carbamate To a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (0.500 g, 1.547 mmol, 1 equiv) in DMF (2 ml), tert-butyl (((1r,4r)-4-aminocyclohexyl)methyl)carbamate 2 (1.060 g, 4.64 mmol, 3 equiv) and sodium tert-butoxide (0.446 g, 4.64 mmol, 3 equiv) were added at room temperature and degassed with nitrogen gas for a period of 15 min. To this reaction mixture, Pd- PEPPSI-Ihept(Cl) (0.075 g, 0.077 mmol), 0.05 equiv) was added under nitrogen condition, degassed for 5 min and stirred at 110 °C 4 h. Upon completion of the reaction (as confirmed by UPLC analysis), the reaction mixture was filtered through Celite bed and washed with CH3CN (5 ml), the filtrate was concentrated under reduced pressure to afford brown thick liquid. The crude compound was purifed by reverse phase chromatography (Grace® column: C1840 µm, 120 g, product eluted with 44% of ACN in 0.1% HCOOH). The pure fraction was lypholized to afford tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl) methyl)carbamate 3 (0.100 g, 0.118 mmol, 7.60 % yield) as a yellow solid.LCMS: 415.2 (M-56). Method :Column: Xbridge C8 (50 × 4.6 mm) 3.5 μm, Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: 0.1% TFA in CAN, Flow Rate: 1.5 ml / min, Area% - 55.37 %.

[0309] Step-2: tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)methyl)carbamate A mixture of tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4 yl)amino)cyclohexyl)methyl)carbamate 3 (0.100 g, 0.213 mmol, 1.0 equiv) and pentanal 4 (0.183 g, 2.125 mmol, 10 equiv) in DCE (1.5 ml) and DMF (1.5 ml) was added TFA (0.033 ml, 0.425 mmol) 2.0 equiv) and stirred for 10 min at 0 °C. To this mixture, sodium triacetoxyborohydride (0.135 g, 0.638 mmol, 3.0 equiv) was added in portions at 0 °C and the resulted colourless cloudy mass was stirred for 16 h at room temperature (monitored by UPLC). Reaction mixture was quenched with ice cold water (5 ml) and extarcted with dichloromethane (3 x 10 ml). The combined organic layer was dried over Na2SO4and concentrated under vaccum to afford crude as a pale yellow liquid. The crude compound was purified by reverse phase chromatography (eluted with 50 % of ACN in 0.1% HCOOH) to afford tert-butyl (((1r,4r)-4-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)(pentyl)amino)cyclohexyl) methyl)carbamate (0.020 g, 0.037 mmol, 17.18 % yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.06 (s, 1H), 7.81 (t, J = 37.20 Hz, 1H), 7.24 (d, J = 6.00 Hz, 2H), 5.26 (d, J = Hz, 1H), 4.72 (t, J = 6.00 Hz, 2H), 3.35 (d, J = 19.60 Hz, 3H), 2.75 (d, J = 6.40 Hz, 3H), 2.33 (d, J = 1.60 Hz, 2H), 1.71 (d, J = 12.00 Hz, 5H), 1.42-1.37 (m, 14H), 0.79 (s, 3H). LCMS: 541.4 (M+H). Method: Column: XBridge C8 (50 × 4.6 mm) 3.5 μm Mobile phase: A: 0.1% TFA in H2O Mobile phase: B: 0.1% TFA in ACN Flow Rate: 1.5 ml / min Area% - 94.78 %. HPLC: Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm Mobile phase: A: 0.1% TFA in water Mobile phase: B: ACN, Flow: 2.0 mL / min, Area% - 98.72 %.

[0310] Step-3: 3-(4-(((1R,4R)-4-(aminomethyl)cyclohexyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To a stirred solution of tert-butyl (((1r,4r)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)cyclohexyl)methyl)carbamate 5 (20 mg, 0.037 mmol) 1.0 equiv) in dichloromethane (1 ml) was added HCl (4M soln. in dioxane, 0.5 ml) at 0 °C and then stirred at room temperature for 2 h .The progress of the reaction was monitored by TLC (10 % MeOH; DCM, Rf~ 0.0. Reaction mixture was concentrated under vaccum at below 40 ºC, to afford off- white solid. The obtained solid was dissolved in water (5 ml) and washed with MTBE (2 × 5 ml), the water layer was lypholized to 3-(4-(((1R,4R)-4-(aminomethyl)cyclohexyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (17 mg, 0.035 mmol, 96 % yield) as off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.86 (br s, 3H), 7.43-7.29 (m, 3H), 5.12 (d, J = 8.80 Hz, 1H), 4.33-4.27 (m, 2H), 3.50-3.30 (m, 2H), 3.12-3.08 (m, 2H), 2.96-2.87 (m, 1H), 2.68-2.59 (m, 3H), 2.04-2.02 (m, 1H), 1.80-1.75 (m, 4H), 1.50-1.48 (m, 3H), 1.21 (s, 6H), 1.00- 0.97 (m, 2H), 0.79 (t, J = 6.40 Hz, 3H). LCMS: 441.3 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: ACN, Flow Rate: 1.5 ml / min, Rt- 1.526 min, Area: 97.05 %. HPLC: Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow: 2.0 mL / min, Rt- 2.287 min, Area :99.27 %.

[0311] Hydrochloride Salt Form of Compound 91

[0312] Step-1: tert-butyl ((1s,4s)-4-formylcyclohexyl)carbamate To a cooled solution of tert-butyl ((1s,4s)-4-(hydroxymethyl)cyclohexyl)carbamate (200 mg, 0.872 mmol, 1 equiv) in DCM (5 ml) was added DMSO (1.5 ml), DIPEA (438 mg, 3.39 mmol, 3.89 equiv) and a solution of pyridine sulfur trioxide (540 mg, 3.39 mmol, 3.89 equiv) in DMSO (1.5 ml) in drops and was stirred at 0 °C for 1h. Upon completion of reaction (as confirmed by TLC (40% ethyl acetate in pet ether, Rf: 0.4), the reaction was quenched with 1.5N HCl (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layer was dried over anhy.Na2SO4and concentrated under vacuum to give the crude product of tert-butyl ((1s,4s)-4- formylcyclohexyl)carbamate 2A (200 mg, 0.880 mmol, 101 % yield) as a colorless liquid.

[0313] Step-2: tert-butyl((1s,4s)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)methyl)cyclohexyl)carbamateTo a solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (200 mg, 0.771 mmol, 1 equiv) and tert-butyl ((1s,4s)-4-formylcyclohexyl)carbamate 2A (210 mg, 0.926 mmol, 5 equiv) in DCE (2 ml) and DMF (0.5 ml) mixture was added TFA (79 mg, 0.694 mmol, 0.9 equiv) and Na(OAc)3BH (245 mg, 1.157 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 12h. Upon completion of the reaction (as confirmed by UPLC) the reaction was quenched with ice water (25 mL) and extracted with DCM (2 x 10 ml). The combined organic layer was concentrated under vacuum to give the crude product which was purified by reverse phase chromatography (Grace® column: generic C18, 40 g snap, 0.1% formic acid in ACN, 20 mL / min, 70-75% ACN in H2O) to give tert-butyl ((1s,4s)-4-(((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamate 3 (105 mg, 0.223 mmol, 28.9 % yield) as an off white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.28 (t, J = 8.00 Hz, 1H), 6.91 (d, J = 7.20 Hz, 1H), 6.73 (d, J = 8.00 Hz, 2H), 5.64 (t, J = 5.20 Hz, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.23 (d, J = 17.20 Hz, 1H), 4.12 (d, J = 17.20 Hz, 1H), 3.49 (s, 1H), 3.03 (t, J = 6.00 Hz, 2H), 2.92 (t, J = 8.00 Hz, 1H), 2.06-2.02 (m, 1H), 1.69 (s, 1H), 1.50 (t, J = 13.20 Hz, 8H), 1.39 (s, 9H). LCMS: 470.0(M+H), Rt (min): 2.306, Area %: 99.775. HPLC: Rt (min): 4.229, Area %: 99.789.

[0314] Step-3: tert-butyl ((1s,4s)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)methyl)cyclohexyl)carbamateTo a solution of tert-butyl ((1s,4s)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)methyl)cyclohexyl)carbamate (90 mg, 0.191 mmol, 1 equiv) in DCE (5 ml) and DMF (0.5 ml) was added pentanal (82 mg, 0.956 mmol, 5 equiv), TFA (19.63 mg, 0.172 mmol, 0.9 equiv) and Na(OAc)3BH (48.6 mg, 0.230 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 12h. Upon completion of the reaction (as confirmed by LCMS) the reaction was quenched with ice water (25 mL) and extracted with DCM (2×10 ml). The combined organic layer was concentrated under vacuum to give the crude product, which was purified by Isolera (column size: Biotage R snap cartridge, KP-Sil, 10g , Silca gel - 230-400 mesh) using 70-80 % ethyl acetate in pet ether. Pure fractions were collected seperately and concentrated under vacuum to give tert-butyl((1s,4s)-4-(((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pentyl)amino)methyl)cyclohexyl)carbamate (30 mg, 0.055 mmol, 29.0 % yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.18 (d, J = 7.20 Hz, 1H), 7.10 (d, J = 8.00 Hz, 1H), 6.66 (d, J = 7.20 Hz, 1H), 5.11 (q, J = 4.80 Hz, 1H), 4.38 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 17.20 Hz, 1H), 3.45 (s, 1H), 3.34-3.16 (m, 2H), 3.11 (d, J = 7.20 Hz, 2H), 2.90 (d, J = 12.00 Hz, 1H), 2.59 (d, J = 19.60 Hz, 2H), 2.02 (t, J = 5.20 Hz, 1H), 1.46 (t, J = 7.20 Hz, 4H), 1.38 (s, 15H), 1.24 (t, J = 10.00 Hz, 5H), 0.84 (t, J = 6.80 Hz, 3H). LCMS: 485.9 (M-56), Rt (min): 2.828, Area %: 99.796. HPLC: Rt (min): 4.910, Area %: 98.887.

[0315] Step-4: 3-(4-((((1s,4s)-4-aminocyclohexyl)methyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, HCl To an ice cold solution of tert-butyl ((1s,4s)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)methyl)cyclohexyl)carbamate (30 mg, 0.055 mmol) in DCM (2 ml) was added HCl (4M in ethyl acetate) (0.5 mL, 16.46 mmol) at 0 °C and stirred for 6 h at room temperature. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture wasconcentrated, washed with MTBE (10mL) to give the crude which was lyophilised to get 3-(4- ((((1s,4s)-4-aminocyclohexyl)methyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (30 mg, 0.063 mmol, 113 % yield) as an off white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.78 (s, 6H), 7.39 (t, J = 8.00 Hz, 1H), 7.22 (d, J = 7.60 Hz, 1H), 7.22 (d, J = 7.60 Hz, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.33 (dd, J = 16.80, 42.40 Hz, 2H), 3.15 (q, J = 7.60 Hz, 5H), 2.05-2.01 (m, 1H), 1.59 (s, 5H), 1.45 (d, J = 5.60 Hz, 6H), 1.25 (d, J = 4.80 Hz, 4H), 0.84 (t, J = 7.20 Hz, 3H). LCMS: 442.0 (M+H), Method: Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Column: Atlantis dC18 (50 × 4.6) 5 μ, Flow Rate: 1.5 ml / min; Rt (min): 1.691, Area %: 99.845. HPLC: Method: Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: ACN, Column: Atlantis dC18 (50 × 4.6 mm) 5 μm, Flow Rate: 1.5 ml / min, Rt (min): 2.839, Area %: 98.026.

[0316] Hydrochloride Salt Form of Compound 92

[0317] Step-1: tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamateTo a cooled solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (500 mg, 2.180 mmol, 1 equiv) in DCM (11 ml) was added DMSO (3.7 ml), DIPEA (0.388 ml, 2.180 mmol, 3.89 equiv) and a solution of pyridine sulfur trioxide (347 mg, 2.180 mmol, 3.89 equiv) in DMSO (3.7 ml) in drops and was stirred at 0 °C for 1h. Upon completion of reaction (as confirmed by TLC (40% ethyl acetate in pet ether, Rf: 0.4), the reaction was quenched with 1.5N HCl (20 mL) and extracted with DCM (2× 20 mL). The combined organic layer was dried over anhy.Na2SO4 and concentrated under vacuum to give the crude product of tert-butyl ((1r,4r)-4- formylcyclohexyl)carbamate 2A (480 mg, 2.112 mmol, 97 % yield) as a yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 3.64-3.50 (m, 1H), 3.16-3.11 (m, 2H), 2.16-2.11 (m, 1H), 1.99 (d, J = 57.60 Hz, 2H), 1.88 (t, J = 24.40 Hz, 3H), 1.38 (s, 10H), 1.18-1.26 (m, 11H). LCMS: 172.4 (M-56), Rt (min): 2.593, Area %: 59.513.

[0318] Step-2: tert-butyl((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)methyl)cyclohexyl)carbamate To a solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (350 mg, 1.350 mmol, 1 equiv) and tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamate 2A (368 mg, 1.620 mmol, 5 equiv) in DCE (1.5 ml) and DMF (0.5 ml) mixture was added TFA (139 mg, 1.215 mmol, 0.9 equiv) and Na(OAc)3BH (429 mg, 2.025 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 12h. Upon completion of the reaction (as confirmed by TLC) the reaction was quenched with ice water (25 mL) and extracted with DCM (2×10 ml). The combined organic layer was concentrated under vacuum to give the crude product which was purified by reverse phase chromatography (Grace®, column: generic C18, 40 g snap, 0.1% formic acid in ACN, 20 mL / min, 70-75% ACN in H2O) and the pure fraction was Lyophilised to give tert-butyl ((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamate 3 (410 mg, 0.834 mmol, 61.8 % yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.27 (t, J = 7.60 Hz, 1H), 6.91 (d, J = 7.60 Hz, 1H), 6.71 (q, J = 8.00 Hz, 2H), 5.62 (t, J = 5.60 Hz, 1H), 5.12 (q, J = 4.80 Hz, 1H), 4.23 (d, J = 17.20 Hz, 1H), 4.12 (d, J = 17.20 Hz, 1H), 3.19 (d, J = 8.00 Hz, 1H), 2.98-2.89 (m, 3H), 2.60 (t, J = 22.00 Hz, 2H), 2.35-2.28 (m, 2H), 2.06-2.02 (m, 1H), 1.81 (t, J = 20.00 Hz, 4H), 1.50 (t, J = 7.20 Hz, 2H), 1.37 (s, 9H), 1.12 (q, J = 11.60 Hz, 3H), 0.99 (t, J = 12.00 Hz, 2H), LCMS: 415.3 (M-56), Rt (min): 2.127, Area %: 95.713. HPLC: Rt (min): 4.211, Area %: 98.834.

[0319] Step-3: tert-butyl ((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)methyl)cyclohexyl)carbamate To a solution of tert-butyl ((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)methyl)cyclohexyl)carbamate (250 mg, 0.531 mmol, 1 equiv) in DCE (2.5 ml) and DMF (0.5ml) was added pentanal (229 mg, 2.66 mmol, 5 equiv), TFA (54.5 mg, 0.478 mmol, 0.9 equiv) and Na(OAc)3BH (169 mg, 0.797 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 12h. Upon completion of the reaction (as confirmed by LCMS), the reaction was quenched with ice water (25 mL) and extracted with DCM (2×10 ml). The combined organic layer was concentrated under vacuum to give the crude product which was purified by Isolera (column size: Biotage R snap cartridge, KP-Sil, 25g , Silca gel - 230-400 mesh) using 70-80 % ethyl acetate in pet ether. Pure fractions were collected seperately and concentrated under vacuum to afford tert-butyl((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pentyl)amino)methyl) cyclohexyl)carbamate 5 (124 mg, 0.229 mmol, 43.2 % yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.37 (t, J = 8.00 Hz, 1H), 7.13 (dd, J = 8.00, 35.00 Hz, 2H), 6.63 (d, J = 8.00 Hz, 1H), 5.09 (t, J = 5.20 Hz, 1H), 4.31 (t, J = 16.80 Hz, 2H), 3.31-3.15 (m, 3H), 3.05-3.03 (m, 2H), 2.00 (s, 1H), 1.72 (d, J = 9.60 Hz, 5H), 1.43-1.36 (m, 14H), 1.26-1.20 (m, 5H), 0.97 (d, J = 27.20 Hz, 4H), 0.83 (t, J = 6.80 Hz, 3H). LCMS: 541.3 (M+H), Rt (min): 2.849, Area %: 95.954. HPLC: Rt (min): 4.907, Area %: 95.462.

[0320] Step-4: 3-(4-((((1r,4r)-4-aminocyclohexyl)methyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, HCl To an ice cold solution of tert-butyl ((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)methyl)cyclohexyl)carbamate (120 mg, 0.222 mmol) in DCM (5 ml) was added HCl (4M in ethyl acetate) (0.12, 3.95 mmol) at 0°C and stirred for 6 h at room temperature. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was concentrated, washed with MTBE (10mL) and dried to 3-(4-((((1r,4r)-4- aminocyclohexyl)methyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl 92 (30 mg, 0.061 mmol, 27.3 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.83 (s, 3H), 7.39 (t, J = 7.60 Hz, 1H), 7.20 (d, J = 7.20 Hz, 1H), 7.11 (d, J = 8.00 Hz, 1H), 5.11 (q, J = 4.80 Hz, 1H), 4.39 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 16.80 Hz, 1H), 3.18 (d, J = 4.80 Hz, 2H), 3.18 (d, J = 4.80 Hz, 2H), 2.93-2.88 (m, 2H), 2.68 (t, J = 2.00 Hz, 1H), 2.62 (d, J = 2.80 Hz, 1H), 2.02 (d, J = 5.60 Hz, 1H), 1.90 (d, J = 10.40 Hz, 2H), 1.77 (d, J = 12.00 Hz, 2H), 1.41 (t, J = 6.80 Hz, 3H), 1.17-1.20 (m, 6H), 0.97 (d, J = 12.00 Hz, 2H), 0.83 (t, J = 6.80 Hz, 3H). LCMS: 441.3 (M+H), Method: Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: ACN, Column: Atlantis dC18 (50 × 4.6 mm) 5 μm, Flow Rate: 1.5 ml / min, Rt (min): 1.695, Area %: 96.479.HPLC: Method: A: 0.1% TFA in H2O, B: ACN, Flow Rate: 2.0 mL / min COLUMN: Xbridge C8(50 × 4.6) mm, 3.5 μm, Rt (min): 2.950, Area %: 95.528.

[0321] Hydrochloride Salt Form of Compound 93

[0322] (E)-3-(4-((4-aminobutyl)(pent-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione hydrochloride

[0323] Step-1: (E)-pent-3-enal To a stirred solution of methyl (E)-pent-3-enoate 2 (2.5 g, 21.90 mmol, 1.0 equiv) in CH2Cl2(50 ml) was added DIBAL-H in hexane (17.52 ml, 17.52 mmol, 0.8 equiv) in drops at -78 °C. Then the resulting reaction mixture was stirred at 78°C for 5 min. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc in pet ether, Rf~ 0.5), the reaction mixture was quenched with 1.5 N HCl solution (10 ml) and extratced with DCM (20 mL). The separated organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and used for next step without concentration

[0324] Step-2: tert-butyl (E)-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pent- 3-en-1-yl)amino)butyl)carbamateTo a stirred solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 1 (0.5 g, 1.161 mmol, 1.0 equiv) and (E)-pent-3-enal 3 (1.954 g, 23.23 mmol, 20.0 equiv) in a mixture of CH2Cl2(10 ml) and DMF (5 ml) was added AcOH (0.332 ml, 5.81 mmol, 5.0 equiv) under nitrogen atmosphereand stirred for 1 h. To this mixture, NaCNBH4 (0.292 g, 4.65 mmol, 4.0 equiv) was added at 0 ºC. The resulting reaction mixture was stirred for over night at room temperature. Upon completion of the reaction (as confirmed by TLC and UPLC analysis, 100% EtOAc, Rf~ 0.7), the reaction mixture was diluted with DCM (30 mL) and washed with water (2 × 30mL), 10% LiCl solution (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to afford crude product as pale yellow liquid. The crude compound was purified by prep-HPLC (Column: X-Bridge-c1819.1X250, Mobile phase: 0.1% FA in Water / ACN, FLOW rate:15 ml / min) to afford tert-butyl (E)-(4-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)(pent-3-en-1-yl)amino)butyl) carbamate 4 (35 mg, 0.068 mmol, 5.87 % yield) as a off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.36-7.40 (m, 1H), 7.18-7.20 (m, 1H), 7.06- 7.08 (m, 1H), 6.78 (s, 1H), 5.40-5.42 (m, 3H), 5.09-5.13 (m, 1H), 4.26-4.42 (m, 2H), 3.41-3.51 (m, 3H), 3.19-3.22 (m, 4H), 2.88-2.92 (m, 3H), 2.11-2.13 (m, 2H), 2.03 (m, 1H), 1.62-1.63 (m, 3H), 1.59-1.60 (m, 2H), 1.37 (s, 9H), LCMS: 499.2 (M+H), Rt (min):2.492, Area-97%.

[0325] Step-3: (E)-3-(4-((4-aminobutyl)(pent-3-en-1-yl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochlorideTo a stirred solution of tert-butyl (E)-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pent-3-en-1-yl)amino)butyl)carbamate 4 (65 mg, 0.130 mmol, 1.0 equiv) in ethyl acetate (1 ml) was added HCl (4M soln. in EtOAc, 2 ml) at 0 °C and then stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC (100% EtOAc). Reaction mixture was concentrated under vaccum at below 40ºC, to afford off-white semi solid. The obtained solid was dissolved in water (2 ml) and washed with MTBE (2 ml), and additional water (2 ml) was added and lypholized to afford (E)-3-(4-((4-aminobutyl)(pent-3-en-1-yl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, HCl (30 mg, 0.067 mmol, 79 % yield) as a off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.84 (s, 3H), 7.09-7.43 (m, 3H), 5.40-5.41 (m, 2H), 5.10-5.14 (m, 1H), 4.32-4.39 (m, 2H), 3.23-3.48 (m, 4H), 2.90-2.93 (m, 1H), 2.74-2.78 (m, 2H), 2.53-2.68 (m, 1H), 2.12-2.14 (m, 2H), 2.02-2.09 (m, 2H), 1.52-1.60 (m, 7H) LCMS: 399.2 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min HPLC: Method: Mobile phase: A: 0.1% FA in water, Mobile phase: B: ACN, Flow: 2.0 mL / min, Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, RT: 2.301 min, Area: 97.652 %.

[0326] Trifluoroacetic Acid Salt Form of Compound 94

[0327] (Z)-3-(4-((4-aminobutyl)(pent-3-en-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione

[0328] Steps-1 & 2: (3-(1-oxo-4-(pent-3-yn-1-ylamino)isoindolin-2-yl)piperidine-2,6- dioneTo a solution of pent-3-yn-1-ol 2 (2.0 g, 23.78 mmol, 1.0 equiv) and CH2Cl2(100 ml) was added Dess-Martin periodinane (11.09 g, 26.2 mmol, 1.1 equiv) and water (0.05 ml) at 0ºC and the resulted white suspension was stirred for 1h at room temperature. Upon completion of the reaction (as confirmed by TLC, 20% EtOAc in pet-ether), the reaction mixture was cooled to -78 ºC and diluted with n-pentane (50 ml) and filtered through silica gel bed. The bed was washed with n-pentane (20 ml) and the filtrate was concentrated to ~50% of the quantity under vaccum at 25ºC , the resulting solution of 3 was used directly for next step. In another RB flask, to a stirred solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6- dione 1 (4.00 g, 15.43 mmol, 0.649 equiv) in DMF (40 ml) was added the above soltuion of 3 at room temperature. Acetic acid (1.753 ml, 30.6 mmol, 1.289 equiv) was added to the reactionmixture and stirred for 2 hours at room temperature. Sodium cyanoborohydride (1.520 g, 24.18 mmol, 1.017 equiv) was added to the reaction mixture at 0 °C and stirred for over night at room temperature. Upon completion of the reaction (as confirmed by TLC and UPLC analysis, 100% EtOAc, Rf~ 0.7), the reaction mixture was diluted with DCM (100 mL) and washed with water (2 × 50 mL), dried over Na2SO4, filtered and concentrated to afford crude product as pale yellow liquid. The crude compound was purified by reverse phase (Grace® column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase, product eluted with 70% of ACN in 0.1% HCO2H) to afford 3-(1-oxo-4-(pent-3-yn-1-ylamino)isoindolin-2-yl)piperidine- 2,6-dione 4 (1.0 g, 3.03 mmol, 12.75% yield)as a pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.30 (t, J = 8.00 Hz, 1H), 6.96 (d, J = 7.20 Hz, 1H), 6.78 (d, J = 6.00 Hz, 1H), 5.72 (t, J = 6.00 Hz, 1H), 5.09-5.14 (m, 1H), 4.23 (d, J = 16.80 Hz, 1H), 4.12 (d, J = 17.20 Hz, 1H), 3.25-3.33 (m, 2H), 2.93 (m, 1H), 2.50-2.51 (m, 1H), 2.40-2.42 (m, 2H), 2.27-2.38 (m, 1H), 2.02-2.06 (m, 1H), 1.75 (t, J = 2.00 Hz, 3H), LCMS: 326.1 (M+H), Rt (min):1.986, Area-98.611%.

[0329] Step-3: tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pent-3-yn-1-yl)amino)butyl)carbamate To a stirred mixture of 3-(1-oxo-4-(pent-3-yn-1-ylamino)isoindolin-2-yl)piperidine-2,6-dione 4 (0.5 g, 1.537 mmol, 1.0 equiv) and tert-butyl (tert-butoxycarbonyl)(5-oxopentyl)carbamate 5 (0.88 g, 3.07 mmol, 2.0 equiv) in CH2Cl2(15 ml) and DMF (15 ml) was added trifluoroacetic acid (0.106 ml, 1.383 mmol, 0.9 equiv) and stirred for 10 min at 0 °C. Sodium triacetoxyborohydride (0.49 g, 2.305 mmol, 1.5 equiv) was added in portions at 0 °C and the resulted colourless cloudy mass was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by UPLC analysis), the reaction mixture was quenched with ice cold water (50 ml) and extracted with dichloromethane (2 × 50 ml). The combined organic layer wasdried over anhy.Na2SO4and concentrated under vaccum to afford the crude product as a brown liquid. The crude compound was purified by (Grace® column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase, product eluted with 70% of ACN in 0.1% HCO2H) to afford tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pent-3-yn-1-yl)amino)butyl)carbamate 10 (0.4 g, 0.649 mmol, 42.2% yield) as a off-white solid1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.39 (t, J = 10.00 Hz, 1H), 7.23 (d, J = 9.60 Hz, 1H), 7.12 (d, J = 10.80 Hz, 1H), 5.08-5.14 (m, 1H), 4.41 (d, J = 22.80 Hz, 1H), 4.31 (d, J = 22.40 Hz, 1H), 3.40-3.47 (m, 2H), 3.23-3.33 (m, 2H), 2.87-2.93 (m, 1H), 2.28-2.45 (m, 1H), 2.01-2.08 (m, 2H), 1.69 (t, J = 2.00 Hz, 3H), 1.49 (s, 18H), 1.27-1.44 (m, 8H), LCMS: 597.4 (M+H), Rt (min):2.482, Area-96.894%.

[0330] Step-4: tert-butyl (Z)-(tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pent-3-en-1-yl)amino)butyl)carbamate To a stirred solution of tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pent-3-yn-1-yl)amino)butyl)carbamate 5 (150 mg, 0.251 mmol, 1.0 equiv), quinoline (39.0 mg, 0.302 mmol, 1.2 equiv) in DMF (2.0 ml) was added Lindlar catalyst (12 mg, 0.113 mmol, 0.449 equiv) and stirred under hydrogen atmosphere at room temperature for 16 h. Upon completion of the reaction (as confirmed by UPLC analysis), the reaction mixture was filtered through Celite bed and washed with DMF (2 ml), the filtrate was purified by reverse phase chromatography (Grace® column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase, product eluted at 70-75% ACN in 0.1% of HCOOH) to afford tert-butyl (Z)-(tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pent-3-en-1-yl)amino)butyl)carbamate 6 (120 mg, 0.182 mmol, 72.2% yield) as a pale yellow gummy solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.39 (t, J = 3.20 Hz, 1H), 7.21 (d, J = 4.80 Hz, 1H), 7.11 (d, J = 8.00 Hz, 1H), 5.38-5.45 (m, 2H), 5.09-5.14 (m, 1H), 4.39 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 17.20 Hz, 1H), 3.36-3.47 (m, 3H), 3.18-3.24 (m, 4H), 3.18-3.20 (m, 1H), 2.50- 2.53 (m, 2H), 2.44-2.50 (m, 1H), 2.16-2.18 (m, 2H), 2.00-2.01 (m, 1H), 1.59 (d, J = 4.80 Hz, 3H), 1.49 (s, 18H), 1.27-1.44 (m, 2H), LCMS: 599.3 (M+H). Method: Column: Atlantis dC18 (50×4.6 mm) 5 μm, Mobile phase:A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min HPLC: Method: Mobile phase: A: 0.1% TFA in water, Mobile phase: B: Methanol, Flow:1.0mL / min, Column: Atlantis dC18 (250×4.6) mm,5μm, RT: 16.959 min, Area :90.666%.

[0331] Step-5: (Z)-3-(4-((4-aminobutyl)(pent-3-en-1-yl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione To a stirred solution of tert-butyl (Z)-(tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pent-3-en-1-yl)amino)butyl)carbamate 6 (60 mg, 0.100 mmol) in CH2Cl2(1 ml) was added TFA (2 ml, 26.0 mmol) at 0 °C and then stirred at room temperature for overnight. Upon completion of the reaction (as confirmed by UPLC), the reaction mixture was concentrated under reduced pressure at 40 ºC, to afford pale yellow thick liquid. The crude compound was purified by preparative HPLC (Column: Atlantis 19x250mm, mobile phase:0.1% TFA in Water / ACN, Flow rate: 2mg / ml) to afford (Z)-3-(4-((4-aminobutyl)(pent-3-en-1- yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, TFA 94 (12 mg, 0.022 mmol, 22.15% yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.61 (s, 3H), 7.41 (t, J = 7.60 Hz, 1H), 7.24 (d, J = 6.80 Hz, 1H), 7.14 (d, J = 7.60 Hz, 1H), 5.44-5.46 (m, 1H), 5.38-5.39 (m, 1H), 5.11-5.15 (m, 1H), 4.39 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 16.80 Hz, 1H), 3.22 (t, J = 8.40 Hz, 4H), 2.79- 2.80 (m, 1H), 2.68-2.77 (m, 2H), 2.63-2.68 (m, 2H), 2.50-2.51 (m, 1H), 2.33-2.34 (m, 2H), 2.17- 2.19 (m, 1H), 1.50 (t, J = 2.00 Hz, 3H), 1.48-1.49 (m, 3H),LCMS: 399.2 (M+H). Method: Column: Atlantis dC18 (50×4.6 mm) 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min HPLC: Method: Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow:1.0mL / min, Column: Atlantis dC18 (250×4.6) mm,5μm, RT: 7.709 min, Area :94.84%.

[0332] Hydrochloride Salt Form of Compound 95

[0333] 3-(4-((4-aminobutyl)(pent-3-yn-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione, HCl

[0334] Steps 1 & 2: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pent-3-yn-1-yl)amino)butyl)carbamate To a solution of pent-3-yn-1-ol 3 (2 g, 23.78 mmol, 1 equiv) in DCM (40 ml) was added Dess- Martin periodinate (11.09 g, 26.2 mmol, 1.1 equiv) at 0 °C and the resulted white suspension was stirred for 1 h at room temperature. The reaction mixture was quenched with a mixture of NaHSO3(5 g) in saturated NaHCO3(50 mL) solution and extracted with DCM (2 x 15 mL). To the combined organic layer was added tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)butyl)carbamate (0.500 g, 1.162 mmol, 1 equiv ) and acetic acid(0.714 g, 11.627 mmol) were added and stired for 2 h. Then NaCNBH3(0.463 g, 11.627 mmol, 10 equiv) was added and allowed to stir for 24 h at room temperature. Upon completion of reaction (confirmed by UPLC), the reaction mixture was quenched with water (40 ml) and extracted with DCM (2× 40 mL). The combined organic layer was dried over anhy. Na2SO4and concentrated under vacuum to get the crude product which was purified by Isolera (Biotage R snap cartridge, KP-Sil, 25 g, 230-400 silica mesh) using 60-70% ethyl acetate in pet ether. The pure fractions were concentrated under vacuum to afford tert-butyl (4-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)(pent-3-yn-1-yl)amino)butyl)carbamate 3 (150 mg, 0.113 mmol, 0.474 % yield) as off white solid. LCMS: 497.2 (M+H), Rt (min): 2.384, Area %: 37.322.

[0335] Step-3:3-(4-((4-aminobutyl)(pent-3-yn-1-yl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, HCl To an ice cold solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pent- 3-yn-1-yl)amino)butyl)carbamate 3 (150 mg, 0.118 mmol, 1 equiv) in DCM (3 ml) was added HCl (4M in ethyl acetate, 0.294 mL, 1.178 mmol, 10 equiv) at 0°C and stirred for 12 h at room temperature. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was concentrated, washed with MTBE (10mL) to give the crude product which was purified by Prep HPLC (Column: X-Bridge-c1819.1X250; Method: 0.1% HCL in Water / ACN; Flow rate:15 ml / min) to afford 3-(4-((4-aminobutyl)(pent-3-yn-1-yl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione, HCl 95 (7.5 mg, 0.017 mmol, 14.16 % yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.78 (s, 1H), 7.41 (t, J = 7.60 Hz, 1H), 7.25 (d, J = 7.20 Hz, 1H), 7.15 (d, J = 8.00 Hz, 1H), 5.15-5.10 (m, 1H), 4.45-4.30 (m, 2H), 3.33 (t, J = 7.20 Hz, 2H), 3.24 (t, J = 6.40 Hz, 3H), 2.93 (s, 1H), 2.77-2.68 (m, 2H), 2.33-2.28 (m, 2H), 2.04(t, J = 5.20 Hz, 1H), 1.70 (t, J = 2.40 Hz, 2H), 1.52 (d, J = 4.00 Hz, 4H), 1.24 (t, J = 3.20 Hz, 1H), 0.84 (t, J = 7.20 Hz, 1H). LCMS: 397.3 (M+H), Method: Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: 0.1% TFA in ACN, Column: X Bridge C8 (50 × 4.6 mm) 3.5 μm, Flow Rate: 1.5 ml / min, Rt (min): 1.340, Area %: 96.271. HPLC: Method: Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Column: X- Bridge C8(50 × 4.6) mm, 3.5 μm, Flow: 2.0 mL / min, Rt (min): 2.314, Area %: 98.115.

[0336] Hydrochloride Salt Form of Compound 96

[0337] 3-(4-(bis(4-aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride

[0338] Step-3: di-tert-butyl (((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)azanediyl)bis(butane-4,1-diyl))dicarbamate To a solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 4 (250 mg, 0.581 mmol), tert-butyl (tert-butoxycarbonyl)(4- oxobutyl)carbamate 5A (334 mg, 1.161 mmol, 2 equiv) and TFA (0.179 ml, 2.323 mmol, 4 equiv) in a mixture of Dichloromethane (0.5 mL, 20 vol) and DMF (0.25 mL, 10 vol) was added sodium triacetoxyborohydride (492 mg, 2.323 mmol, 4 equiv) and stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, EtOAc, Rf~ 0.6,and UPLC), the reaction mixture was diluted with DCM (5 mL) and washed water (3 x 10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated. The resulted residue was purified by chromatography (column size: Biotage R snap cartridge, KP-Sil, 25 g, 230-400 silica gel) using 75-80 % ethyl acetate in pet ether to obtain tert-butyl (tert-butoxycarbonyl)(4-((4- ((tert-butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl) carbamate 5 (150 mg, 36.5 % yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.20 (d, J = 7.20 Hz, 1H), 7.08 (d, J = 8.00 Hz, 1H), 6.78 (d, J = 5.20 Hz, 1H), 5.11 (q, J = 5.20 Hz, 1H), 4.39 (d, J = 17.20 Hz, 1H), 4.28 (d, J = 16.80 Hz, 1H), 3.34 (s, 2H), 3.18 (d, J = 6.80 Hz, 4H), 2.90 (s, 4H), 2.00 (s, 2H), 1.40 (s, 33H). LC-MS: 702.4 (M+H), Rt (min): 2.83, Area%: 99.289.

[0339] Step-4: 3-(4-(bis(4-aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride To an ice cold solution of di-tert-butyl (((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)azanediyl)bis(butane-4,1-diyl))dicarbamate 5 (150 mg, 0.249 mmol) in DCM (5 mL) was added HCl (4M soln. in dioxane) (3 ml, 12.00 mmol) and stirred for 2 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc), the reaction mixture was concentrated and lyophilized to afford 3-(4-(bis(4-aminobutyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl 96 (82 mg, 67.8 % yield) (2.4 g, 98 %) as pale- yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.07 (s, 6H), 7.52 (s, 3H), 5.12 (q, J = 5.20 Hz, 1H), 4.65 (s, 8H), 3.42-3.43 (m 1H), 2.74 (d, J = 5.20 Hz, 4H), 2.62 (d, J = 16.80 Hz, 1H), 2.07 (t, J = 5.60 Hz, 1H), 1.56 (d, J = 4.80 Hz, 8H).1H-NMR (400 MHz, CD3OD): δ 7.93 (s, 2H), 7.80 (s, 1H), 5.24 (q, J = 4.80 Hz, 1H), 4.48 (q, J = 400.80 Hz, 2H), 3.66 (t, J = 26.40 Hz, 4H), 3.00-2.92 (m, 6H), 2.68-2.61 (m, 1H), 2.28-2.24 (m, 1H), 1.69 (s, 1H). LCMS: 402.3 (M+H). Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: 0.1 % TFA in ACN. Flow rate:1.5 ml / min. Column: XBridge C8 (50 × 4.6 mm) 3.5 μm. Rt (min): 0.887; Area %: 97.781. HPLC: Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 2.0 mL / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. Rt (min): 1.08; Area%: 95.532.

[0340] Hydrochloride Salt Form of Compound 97

[0341] 3-(4-((4-aminobutyl)(3-aminopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione dihydrochloride

[0342] Step-1: tert-butyl (3-oxopropyl)carbamate A solution of oxalyl chloride (0.599 ml, 6.85 mmol, 1.2 equiv) in DCM (10 mL) was added dropwise to a solution of DMSO (0.972 ml, 13.70 mmol, 2.4 equiv) in DCM (5 mL) at -78°C over a period of 15 minutes under nitrogen atmosphere and stirred for 15 minutes at the same temperature. To this a solution of tert-butyl (3-hydroxypropyl)carbamate 5 (1 g, 5.71 mmol, 1 equiv) in DCM (5 mL) was added dropwise over a period of 15 minutes. After stirring thereaction mixture for 30 minutes at -78°C, was added TEA (3.98 ml, 28.5 mmol, 5.0 equiv) in drops at -78°C. Once addition was complete, the reaction mixture was slowly warmed to 0°C and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, 3:7 / EtOAc: pet ether, Rf~ 0.4, KMnO4), the reaction mixture was diluted with DCM (10 mL) and washed with 10% aq citric acid solution (1 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure below 30°C to afford crude tert-butyl (3-oxopropyl)carbamate 6 (0.950 g, 4.90 mmol, 86 % yield) as pale yellow liquid which was used further without purification. LCMS: (mass peak not observed). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.644; Area% - 89.26.

[0343] Step-2: tert-butyl (4-((3-((tert-butoxycarbonyl)amino)propyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamatetert-butyl (3-oxopropyl)carbamate 6 (0.805 g, 4.65 mmol, 4 equiv) and of tert-butyl (4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 4 (0.5 g, 1.161 mmol, 1 equiv) were taken together in a mixture of 1,2-Dichloroethane (10 mL, 10 vol) and DMF (5 mL, 5 vol) under nitrogen atmosphere. To this, acetic acid (0.332 ml, 5.81 mmol, 5 equiv) was added and the reaction mixture was stirred for 1 hour at room temperature. NaCNBH3(0.292 g, 4.65 mmol, 4 equiv) was added in portions and the reaction mixture was stirred for additional 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf ~ 0.5, and LCMS), the reaction mixture was diluted with ice-cold water (15 mL), extracted with DCM (2 x 15 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford crude product as white solid, which was purified by Prep- HPLC (Method: Instrument: SC-DC-ARD-05-045; column no: XBridge C8 - 250-X-Select-C18-19x150mm; 0.1% TFA in Water / ACN; Rt: 9.6 min) and lyophilized to obtain tert-butyl (4-((3- ((tert-butoxycarbonyl)amino)propyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 7 (60 mg, 0.092 mmol, 7.89 % yield) as white solid. LCMS: 588.4 (M+H). Method: Column: XBridge C8(50 × 4.6 mm)3.5 μm Mobile phase: A: 0.1% TFA in H2O B: 0.1% TFA in ACN, Flow Rate: 1.5 mL / min. Rt (min): 1.911; Area% - 89.75.1H-NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.14 (d, J = 7.20 Hz, 1H), 7.08 (d, J = 8.00 Hz, 1H), 6.82-6.76 (m, 2H), 5.10 (dd, J = 5.20, 13.20 Hz, 1H), 4.35 (q, J = 17.20 Hz, 2H), 3.20-3.16 (m, 4H), 2.96-2.89 (m, 5H), 2.04-2.01 (m, 1H), 1.58-1.51 (m, 2H), 1.58-1.51 (m, 23H).

[0344] Step-3: 3-(4-((4-aminobutyl)(3-aminopropyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione dihydrochloride To an ice cold solution of tert-butyl (4-((3-((tert-butoxycarbonyl)amino)propyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 7 (60 mg, 0.102 mmol, 1 equiv) in ethyl acetate (2 mL) was added HCl (4M soln. in EtOAc, 4 mL) and stirred for 1.5 h at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated, washed with MTBE (2 × 5 mL) and lyophilized to afford 3-(4-((4- aminobutyl)(3-aminopropyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 97 (20 mg, 0.051 mmol, 50.1 % yield) as off white solid. LCMS: 388.3 (M-2×HCl). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate :0.6 mL / min. Rt (min): 2.218; Area% - 99.01. HPLC: 93.99 %, Rt (min): 6.421. Method: Column: Atlantis dC18 (250 × 4.6) mm, 5 μm, Mobile Phase A: 0.1% TFA in H2O, Mobile Phase B: Methanol, Flow rate:1.0 mL / min.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.94 (br s, 6H), 7.43 (t, J = 7.60 Hz, 1H), 7.29-7.21 (m, 2H), 5.13 (dd, J = 4.80, 13.20 Hz, 1H), 4.45 (d, J = 17.20 Hz, 1H), 4.31 (d, J = 16.80 Hz, 1H), 3.76-3.20 (m, 4H), 2.98-2.89 (m, 1H), 2.81-2.76 (m, 4H), 2.59 (s, 2H), 2.08-2.02 (m, 1H), 1.76-1.72 (m, 2H), 1.53 (s, 4H).

[0345] Hydrochloride Salt Form of Compound 102

[0346] 3-(4-((4-aminobutyl)((1S,4S)-4-aminocyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione dihydrochloride

[0347] Step-1: tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)carbamate 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (0.5 g, 1.547 mmol, 1 equiv), tert-butyl ((1S,4S)-4-aminocyclohexyl)carbamate 2 (0.995 g, 4.64 mmol, 3 equiv) and NaOt-Bu (0.446 g,4.64 mmol, 3 equiv) were dissolved in DMF (2 ml) and de-gassed for 20 min with nitrogen. Pd- PEPPSI-IHept(Cl) (0.075 g, 0.077 mmol, 0.05 equiv) was added under nitrogen atmosphere and heated the reaction at 110 °C for 4 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.4, and LCMS), the reaction mixture was filtered through Celite bed, washed with THF (10 mL), concentrated to minimum volume (3 mL) and purified by reverse-phase column chromatography (Grace® column: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase) to obtain tert-butyl ((1S,4S)-4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl)carbamate 3 (138 mg, 0.289 mmol, 18% yield) as pale yellow solid. LCMS: 456.0 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.223; Area% - 95.48.1H-NMR (400 MHz, DMSO-d6): δ 11.04 (s, 1H), 7.28 (t, J = 7.60 Hz, 1H), 6.79 (d, J = 8.00 Hz, 1H), 6.63 (br s, 1H), 5.17-5.09 (m, 2H), 4.21 (q, J = 17.20 Hz, 2H), 3.47-3.42 (m, 2H), 2.98-2.90 (m, 1H), 2.68-2.65 (m, 1H), 2.08-2.03 (m, 1H), 1.66 (m, 6H), 0.54 (m, 3H), 1.39 (m, 10H).

[0348] Step-2: tert-butyl (tert-butoxycarbonyl)(4-(((1S,4S)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate To a solution of tert-butyl ((1S,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino) cyclohexyl)carbamate 3 (130 mg, 0.285 mmol, 1 equiv), tert-butyl (tert-butoxycarbonyl)(4- oxobutyl)carbamate 4 (0.164 g, 0.569 mmol, 2 equiv) in DCM (4 ml) and DMF (4 ml) at 0 °C were added TFA (0.074 ml, 1.139 mmol, 4 equiv ) followed by sodium triacetoxyborohydride (0.241 g, 1.139 mmol, 4 equiv). The reaction mixture was warmed to RT and stirred at the same temperature for 16 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.5, and LCMS), the reaction mixture was diluted with ice-cold water (15 mL),extracted with ethyl acetate (2 x 15 mL), washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions from the column were lyophilized to afford tert-butyl (tert-butoxycarbonyl)(4-(((1S,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 5 (74 mg, 0.140 mmol, 58% yield) as white solid. LCMS: 726.7 (M-H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.912; Area% - 99.75.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.40 (t, J = 7.60 Hz, 1H), 7.26 (dd, J = 8.00, 16.60 Hz, 2H), 6.97 (d, J = 7.60 Hz, 1H), 6.97 (q, J = 7.60 Hz, 1H), 4.30 (q, J = 17.20 Hz, 2H), 3.56 (m, 1H), 3.36-3.16 (m, 2H), 3.08 (m, 1H), 2.91-2.88 (m, 1H), 2.01-1.99 (m, 1H), 1.785 1.809 (m, 2H), 1.65-1.62 (m, 3H), 1.53 (m, 8H), 1.44-1.40 (m, 27H), 1.24-1.21 (m, 3H).

[0349] Step-3: 3-(4-((4-aminobutyl)((1S,4S)-4-aminocyclohexyl)amino)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione dihydrochloride To an ice cold solution of tert-butyl (tert-butoxycarbonyl)(4-(((1S,4S)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 5 (72 mg, 0.099 mmol, 1 equiv) in DCM (1 mL) was added HCl (4M soln. in EtOAc, 2.5 mL) and stirred for 2 h at room temperature. The progress of the reaction was monitored by LCMS. The reaction mixture was concentrated, washed with MTBE (2 × 5 mL) and lyophilized to afford 3-(4-((4-aminobutyl)((1S,4S)-4-aminocyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride 102 (49 mg, 0.095 mmol, 96 % yield) as off white solid.LCMS: 427.2 (M-HCl). Method: Column: XBridge C8 (50 × 4.6 mm) 3.5 μm Mobile phase: A: 0.1% TFA in H2O B: 0.1% TFA in ACN, Flow Rate: 1.5 mL / min. Rt (min): 0.932; Area% - 94.26. HPLC: 95.86 %, Rt (min): 1.363. Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5μ m, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow: 2.0 mL / min.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.23 (s, 3H), 7.92 (s, 3H), 7.44 (d, J = 7.20 Hz, 3H), 5.10 (dd, J = 5.20, 12.80 Hz, 1H), 4.47-4.29 (m, 2H), 3.25 (s, 4H), 2.73-2.70 (m, 1H), 2.68-2.68 (m, 4H), 2.05-2.02 (m, 1H), 1.92-1.83 (m, 4H), 1.92-1.83 (m, 6H), 1.32 (s, 2H).

[0350] Hydrochloride Salt Form of Compound 103

[0351] 3-(4-((4-aminobutyl)((1r,4r)-4-aminocyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, 2HCl

[0352] Step-1: tert-butyl ((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)carbamate3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (0.5 g, 1.547 mmol, 1 equiv), tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate 2 (0.995 g, 4.64 mmol, 3 equiv) and NaOt-Bu (0.446 g, 4.64 mmol, 3 equiv) were dissolved in DMF (2 ml) and de-gassed for 20 min with nitrogen. Pd- PEPPSI-IHept(Cl) (0.075 g, 0.077 mmol, 0.05 equiv) was added under nitrogen atmosphere and heated the reaction at 110 °C for 4 h. Upon completion of the reaction (as confirmed by UPLC analysis, the reaction mixture was filtered through celite, washed with THF (10 mL), concentrated to minimum volume (3 mL) and purified by reverse-phase column chromatography (Grace® column: C1840 µm, 100 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase) to obtain tert-butyl ((1R,4S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)carbamate 3 (0.070 g, 0.152 mmol, 9.81 % yield) as cream colour solid. LCMS: 401.1 (M-Boc). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.200, Area% - 99.011H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.27 (t, J = 7.20 Hz, 1H), 6.91 (d, J = 7.20 Hz, 1H), 6.80 (t, J = 8.00 Hz, 2H), 5.29 (d, J = 6.80 Hz, 1H), 5.12 (q, J = 4.80 Hz, 1H), 4.16 (q, J = 17.20 Hz, 2H), 2.93-2.89 (m, 1H), 2.70-2.60 (m, 2H), 2.30-2.20 (m, 2H), 2.09-1.99 (m, 3H), 1.80 (m, 2H), 1.39 (s, 9H), 1.32-1.24 (m, 4H).

[0353] Step-2: tert-butyl (tert-butoxycarbonyl)(4-(((1R,4R)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamateTo a solution of tert-butyl ((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino) cyclohexyl)carbamate 3 (70 mg, 0.153 mmol, 1 equiv), tert-butyl (tert-butoxycarbonyl)(4- oxobutyl)carbamate 4 (88 mg, 0.307 mmol, 2 equiv) in DCM (5 ml) and DMF (0.5 ml) at 0 °C was added TFA (0.047 ml, 0.613 mmol, 4 equiv) followed by sodium triacetoxyborohydride (130 mg, 0.613 mmol, 4 equiv). The reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.5, and LCMS), the reaction mixture was diluted with ice-cold water (15 mL), extracted with DCM (2 x 10 mL), washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The resulted residue was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 100 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions from the column were lyophilized to afford tert-butyl (tert-butoxycarbonyl)(4-(((1R,4R)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 5 (40 mg, 0.055 mmol, 35.8 % yield) as white solid. LCMS: 728.5 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.913; Area% - 99.75.

[0354] Step-3: 3-(4-((4-aminobutyl)((1R,4R)-4-aminocyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HClTo an ice cold solution of tert-butyl (tert-butoxycarbonyl)(4-(((1r,4r)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 5 (40 mg, 0.055 mmol, 1 equiv) in DCM (1 mL) was added HCl (4M soln. in EtOAc, 1 mL, 4.0 mmol) and stirred for 2 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 10% MeOH / DCM, Rf~ 0.1), the reaction mixture was concentrated, washed with MTBE (2 × 5 mL) and further lyophilized to afford 3-(4-((4- aminobutyl)((1r,4r)-4-aminocyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl 103 (13.2 mg, 0.026 mmol, 47.8 % yield) as off white solid. LCMS: 428.3 (M+H) Method: Column: XBridge C8 (50 × 4.6 mm) 3.5 μm Mobile phase: A: 0.1% TFA in H2O Mobile phase: B: 0.1% TFA in ACN, Flow Rate: 1.5 ml / min, Rt (min): 0.906; Area% - 95.74. HPLC: 99.63 %, Rt (min): 11.860. Method: Column: Atlantis dC18(250 × 4.6) mm, 5 μm, Mobile phase A: 0.1% TFA in water, Mobile phase B: Methanol, Flow rate: 0.7 ml / min1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.96 (s, 3H), 7.80 (s, 3H), 7.44 (d, J = 7.20 Hz, 1H), 7.34 (t, J = 8.80 Hz, 2H), 5.12 (q, J = 5.20 Hz, 1H), 4.38-4.23 (m, 2H), 3.13 (s, 2H), 2.98-2.89 (m, 3H), 2.68 (q, J = 1.60 Hz, 2H), 2.61 (d, J = 18.00 Hz, 2H), 2.04-1.91 (m, 3H), 1.78 (s, 2H), 1.62-1.50 (m, 4H), 1.45 (t, J = 25.60 Hz, 4H).

[0355] Hydrochloride Salt Form of Compound 104

[0356] 3-(4-((4-aminobutyl)((1s,4s)-4-(aminomethyl)cyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride

[0357] Step-1:tert-butyl(((1s,4s)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino) cyclohexyl)methyl)carbamate To a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (1.0 g, 3.09 mmol, 1.0 equiv) in DMF (5 ml, 5 vol), tert-butyl(((1s,4s)-4-aminocyclohexyl) methyl)carbamate 2 (1.060 g, 4.64 mmol, 1.5 equiv) and sodium tert-butoxide (0.892 g, 9.28 mmol, 3.0 equiv) were added at room temperature and degassed by bubbling with nitrogen gas for a period of 15 min. To this reaction mixture, Pd-PEPPSI-IHept(Cl) (0.151 g, 0.155 mmol), 0.05 equiv) was added under nitrogen atmosphere, degassed for 5 min and the mixture was stirred at 85 °C for overnight. Upon completion of the reaction (as confirmed by TLC and UPLC analysis, 100% EtOAc, Rf ~ 0.5).The reaction mixture was filtered through Celite bed and washed with THF (50 ml), the filtrate was concentrated under reduced pressure to afford brown thick liquid. The crude compound was purifed by reverse phase chromatography (product eluted with 75% of ACN in 0.1% HCO2H). The pure fraction was lyophilized to afford tert-butyl (((1s,4s)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl)methyl) carbamate 3 (0.2 g, 0.350 mmol, 11.30 % yield) as a pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.25-7.29 (m, 1H), 6.90-6.93 (m, 1H), 6.80- 6.87 (m, 1H), 6.77-6.79 (m, 1H), 5.11-5.21 (m, 2H), 4.15-4.30 (m, 2H), 3.47-3.51 (m, 1H), 2.92- 2.99 (m, 3H), 2.67-2.68 (m, 1H), 2.30-2.34 (m, 1H), 2.02-2.08 (m, 1H), 1.41-1.46 (m, 3H), 1.38 (m, 15H). LCMS: 415.8 (M-tBu), Rt (min):2.324, Area-89.8%. HPLC: Rt (min): 5.496; Area - 82.3%.

[0358] Step-2: tert-butyl (tert-butoxycarbonyl)(4-oxobutyl)carbamate A solution of oxalyl chloride (1.815 ml, 20.73 mmol, 2.0 equiv) in DCM (20 mL) was added dropwise to a solution of DMSO (2.94 ml, 41.5 mmol, 4.0 equiv) in DCM (5 mL) at -78 °C over a period of 15 min under nitrogen atmosphere and stirred for 15 min at the same temperature. To this, a solution of tert-butyl (tert-butoxycarbonyl)(4-hydroxybutyl)carbamate 4 (3.0 g, 10.37 mmol) in CH2Cl2(5 ml) was added dropwise over a period of 15 min. After stirring the reaction mixture for 30 minutes at -78 °C, triethylamine (8.67 ml, 62.2 mmol, 6.0 equiv) was added in drops at -78 °C. Then, the reaction mixture was slowly warmed to 0 °C and stirred for 30 min. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc / pet ether, Rf~ 0.6, KMnO4), the reaction mixture was diluted with DCM (40 mL) and washed with 10% aq citric acid solution (1 x 40 mL), and water (1 x 40 mL), dried over Na2SO4, filtered and concentrated under vacuum (below 30°C) to afford of tert-butyl (tert-butoxycarbonyl)(4-oxobutyl)carbamate 5 (2.9 g, 9.99 mmol, crude) as pale yellow liquid which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 3.47-3.50 (m, 1H), 2.51-2.55 (m, 2H), 2.42- 2.44 (m, 2H), 1.69-1.75 (m, 2H), 1.43-1.45 (s, 18H),

[0359] Step-3: tert-butyl (tert-butoxycarbonyl)(4-(((1s,4s)-4-(((tert-butoxycarbonyl) amino) methyl)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamateA mixture of tert-butyl (((1s,4s)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)methyl)carbamate 3 (0.2 g, 0.425 mmol, 1.0 equiv) and tert-butyl (tert- butoxycarbonyl)(4-oxobutyl)carbamate 5 (0.244 g, 0.850 mmol, 2.0 equiv) in CH2Cl2 (10 ml) and DMF (10.00 ml) was added trifluoroacetic acid (0.131 ml, 1.700 mmol, 4.0 equiv) and stirred for 10 min at 0 °C. Sodium triacetoxyborohydride (0.360 g, 1.700 mmol, 4.0 equiv) was added in portions at 0 °C and the resulted colourless cloudy mass was stirred for 16 h at room temperature (monitored by UPLC). Reaction mixture was cooled to 0 °C and additional quantity of tert-butyl (tert-butoxycarbonyl)(4-oxobutyl)carbamate 5 (0.244 g, 0.850 mmol, 2.0 equiv), trifluoroacetic acid (0.131 ml, 1.700 mmol, 4.0 equiv) were added and stirred for 10 min. Then, sodium triacetoxyborohydride (0.360 g, 1.700 mmol, 4.0 equiv) was added in portions at 0 °C and the resulted colourless cloudy mass was stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 8: 2 / EtOAc: pet ether, Rf ~ 0.6), the reaction mixture was quenched with ice cold water (20 ml) and extarcted with dichloromethane (2 × 50 ml). The combined organic layer was dried over anhy.Na2SO4and concentrated under vaccum to afford the crude product as a pale yellow liquid. The crude compound was purified by Isolera chromatography (Biotage R snap cartridge, KP-Sil, 100 g, 230-400 silica gel) using 60-70 % of ethyl acetate in pet ether. The fractions were collected and concentrated under vaccum to get a pale yellow liquid. The obtained compound was further purified by reverse phase chromatography (eluted with 75% of ACN in 0.1% HCO2H), and the pure fraction was lypholized to afford tert-butyl (tert- butoxycarbonyl)(4-(((1s,4s)-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl) (2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 6 (0.11 g, 0.146 mmol, 34% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1H), 7.40-7.43 (m, 1H), 7.27-7.33 (m, 2H), 6.78- 6.81 (m, 1H), 5.07-5.12 (m, 1H), 4.24-4.36 (m, 2H), 3.33-3.39 (m, 2H), 3.08-3.12 (m, 3H), 2.91- 2.95 (m, 3H), 2.60-2.61 (m, 2H), 2.53-2.56 (m, 2H), 1.98-2.01 (m, 1H), 1.62-1.65 (m, 3H), 1.52- 1.53 (m, 6H), 1.48 (m, 27H), 1.22-1.24 (m, 2H). LCMS: 741.4 (M+), Rt (min):2.945, Area%- 89.8%. HPLC: Rt (min): 5.816; Area% - 99.9%.

[0360] Step-4: 3-(4-((4-aminobutyl)((1s,4s)-4-(aminomethyl)cyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochoride To a stirred solution of tert-butyl(tert-butoxycarbonyl)(4-(((1s,4s)-4-(((tert-butoxycarbonyl) amino)methyl)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl) carbamate 6 (0.1 g, 0.135 mmol, 1.0 equiv) in dichloromethane (10 ml) was added HCl (4M soln. in dioxane, 10 ml) at 0 °C and then stirred at room temperature for 2 h .The progress of the reaction was monitored by LCMS. Reaction mixture was concentrated under vaccum at below 40 ºC, to afford off-white solid. The obtained solid was dissolved in water (10 ml) and washed with MTBE (2 x 10 ml), the water layer was lypholized to afford 3-(4-((4-aminobutyl)((1s,4s)-4- (aminomethyl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl (62.5 mg, 0.116 mmol, 86% yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.89-7.98 (m, 6H), 7.33-7.44 (m, 3H), 5.10- 5.13 (m, 1H), 4.30-4.37 (m, 2H), 3.43-3.49 (m, 2H), 3.14-3.17 (m, 2H), 2.84-2.96 (m, 6H), 2.05 (m, 1H), 1.86 (m, 2H), 1.32-1.64 (m, 9H), 1.24 (m, 2H). LCMS: 442.3 (M+H). Method: Column: XBridge C8 (50 × 4.6 mm) 3.5 μm, Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: 0.1% TFA in Acetonitrile, Flow Rate: 1.5 ml / min. HPLC: Method: Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Methanol, Flow rate: 1.0 ml / min. Column: Atlantis dC18 (250 × 4.6) mm, 5 μm. RT: 6.488 min, Area :95.427 %.

[0361] Hydrochloride Salt Form of Compound 105

[0362] 3-(4-((4-aminobutyl)((1R,4R)-4-(aminomethyl)cyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl

[0363] Step-1: tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)cyclohexyl)methyl)carbamate 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (1.0 g, 3.09 mmol, 1 equiv), tert-butyl (((1R,4R)-4-aminocyclohexyl)methyl)carbamate 2 (2.120 g, 9.28 mmol, 3 equiv) and NaOt-Bu (0.892 g, 9.28 mmol, 3 equiv) were dissolved in DMF (4 ml) and de-gassed for 20 min with nitrogen. Pd-PEPPSI-IHept(Cl) (0.151 g, 0.155 mmol, 0.05 equiv) was added under nitrogen atmosphere and heated the reaction at 110 °C for 4 h. Upon completion of the reaction (as confirmed by UPLC analysis, the reaction mixture was filtered through celite, washed with EtOAc (5 mL), concentrated to minimum volume (3 mL) and purified by reverse-phase column chromatography (Grace® column: C1840 µm, 100 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase) to obtain tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)cyclohexyl)methyl)carbamate 3 (50 mg, 0.102 mmol, 3.30 % yield) as a pale yellow solid. LCMS: 401.1 (M-Boc). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm Mobile phase: A: 0.1% FA in H2O B: ACN, Flow Rate: 1.5 mL / min. Rt (min): 2.262, Area% - 96.251H-NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.26 (t, J = 7.60 Hz, 1H), 6.91 (d, J = 7.60 Hz, 1H), 6.85-6.78 (m, 2H), 5.28 (d, J = 8.40 Hz, 1H), 5.12 (dd, J = 5.20, 13.20 Hz, 1H), 4.16 (d, J =17.2 Hz, 2H), 4.09 (d, J = 17.2 Hz, 1H), 2.66 (t, J = 14.40 Hz, 1H), 2.34-2.27 (m, 1H), 2.04- 1.99 (m, 3H), 1.73-1.70 (m, 2H), 1.38 (s, 11H), 1.29-1.14 (m, 2H), 1.05-1.03 (m, 2H)

[0364] Step-2: tert-butyl (tert-butoxycarbonyl)(4-(((1R,4R)-4-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate To a solution of tert-butyl (((1R,4R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino)cyclohexyl) methyl)carbamate 3 (90 mg, 0.191 mmol, 1 equiv), tert-butyl (tert- butoxycarbonyl)(4-oxobutyl)carbamate 4 (110 mg, 0.383 mmol, 2 equiv) DCM (5 ml) and DMF (2 mL) at 0 °C were added TFA (0.059 ml, 0.765 mmol, 4 equiv) and sodium triacetoxyborohydride (162 mg, 0.765 mmol, 4 equiv). The resulted reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was diluted with ice-cold water (10 mL), extracted with DCM (2 x 10 mL), washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The resulted residue was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 100 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions from the column were lyophilized to afford tert-butyl (tert-butoxycarbonyl)(4-(((1R,4R)-4-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 5 (20 mg, 0.025 mmol, 14.03 % yield) as white solid.LCMS: 742.5 (M+H). Method: Column: XBridge C8 (50 × 4.6 mm) 3.5 μm, Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: 0.1% TFA in ACN, Flow Rate: 1.5 ml / min. Rt (min): 2.238; Area% - 98.70.1H-NMR (400 MHz, DMSO-d6): δ 10.97 (s, 1H), 7.40 (t, J = 7.60 Hz, 1H), 7.26 (q, J = 8.00 Hz, 2H), 6.83-6.82 (m, 1H), 5.09 (q, J = 4.80 Hz, 1H), 3.12 (t, J = 6.00 Hz, 2H), 3.00 (m, 2H), 2.90 (d, J = 3.60 Hz, 2H), 1.70 (d, J = 9.60 Hz, 4H), 1.69-1.38 (m, 4H), 1.24 (s, 33H), 1.19 (d, J = 9.20 Hz, 2H), 0.87 (q, J = 6.00 Hz, 2H).

[0365] Step-3: 3-(4-((4-aminobutyl)((1R,4R)-4-(aminomethyl)cyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl To an ice cold solution of tert-butyl (tert-butoxycarbonyl)(4-(((1r,4r)-4-(((tert-butoxycarbonyl) amino)methyl)cyclohexyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl) carbamate (20 mg, 0.027 mmol)1 equiv) in DCM (1 mL) was added HCl (4M soln. in EtOAc, 1 mL, 4.0 mmol) and stirred for 2 h at room temperature. Upon completion of the reaciton by TLC analysis (10% MeOH:DCM, Rf~ 0.1), the reaction mixture was concentrated, and lyophilized to afford 3-(4-((4-aminobutyl)((1R,4R)-4-(aminomethyl)cyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, 2HCl (7.5 mg, 0.014 mmol, 52.3 % yield) as a pale yellow solid. LCMS: 428.3 (M+H) Method: Column: XBridge C8 (50 × 4.6 mm) 3.5 μm, Mobile phase: A: 0.1% TFA in H2O, Mobile phase: B: 0.1% TFA in CAN, Flow Rate: 1.5 ml / min, Rt (min): 0.8 / 66; Area% - 94.61. HPLC: 96.75 %, Rt (min): 2.674. Method: Method info: A: 0.1% TFA in H2O, B: Methanol, Flow Rate:1.0ml / min, COLUMN: YMC Hydrosphere C18 (150 × 4.6 mm),3 μm1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.87-7.86 (m, 6H), 7.44 (s, 1H), 7.33 (s, 2H), 5.13-5.09 (m, 1H), 4.31 (q, J = 16.40 Hz, 2H), 3.13 (s, 2H), 2.98 (t, J = 6.00 Hz, 1H), 2.89 (d, J= 5.20 Hz, 1H), 2.71 (s, 2H), 2.68 (d, J = 1.60 Hz, 3H), 2.03 (d, J = 10.80 Hz, 1H), 1.7-1.9 (m, 4H), 1.53 (t, J = 7.20 Hz, 5H), 1.24-1.25 (m, 2H), 1.12-1.0 (m, 2H).

[0366] Hydrochloride Salt Form of Compound 106

[0367] 3-(4-((4-aminobutyl)(((1s,4s)-4-aminocyclohexyl)methyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl

[0368] Step-1: tert-butyl ((1s,4s)-4-formylcyclohexyl)carbamate To a cooled solution of tert-butyl ((1s,4s)-4-(hydroxymethyl)cyclohexyl)carbamate (500 mg, 2.180 mmol, 1 equiv) in DCM (11 ml) was added DMSO (3.7 ml), DIPEA (1.510 ml, 8.48 mmol, 3.89 equiv) and a solution of pyridine sulfur trioxide (1.35 g, 8.48 mmol, 3.89 equiv) in DMSO (1.5 ml) in drops and was stirred at 0 °C for 1 h. Upon completion of reaction (as confirmed by TLC (40% ethyl acetate in pet ether, Rf: 0.4), the reaction was quenched with 1.5 N HCl (20 mL) and extracted with DCM (2× 20 mL). The combined organic layer was dried over anhy.Na2SO4and concentrated under vacuum to give the crude of tert-butyl ((1s,4s)-4- formylcyclohexyl)carbamate 2A (360 mg, 1.584 mmol, 72.6 % yield) as a colorless liquid.1H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.23 (s, 1H), 6.74 (s, 1H), 3.65-3.56 (m, 2H), 2.55-2.50 (m, 13H), 1.41 (s, 3H).

[0369] Step-2: tert-butyl ((1s,4s)-4-(((4-((tert-butoxycarbonyl)amino)butyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamateTo a solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate Int-4 (200 mg, 0.465 mmol, 1 equiv) and tert-butyl ((1r,4r)-4- formylcyclohexyl)carbamate 2A (528 mg, 2.323 mmol, 5 equiv) in DCE (2 ml) and DMF (0.5 ml) mixture was added TFA (47.7 mg, 0.418 mmol, 0.9 equiv) and Na(OAc)3BH (35.0 mg, 0.557 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 12h. Upon completion of the reaction (as confirmed UPLC) the reaction mixture was quenched with ice water (25 mL) and extracted with DCM (2 x 10 ml). The combined organic layer was concentrated under vacuum to get the crude product. The crude product was purified by reverse phase chromatography (Grace® column: generic C18, 40 g snap, 0.1% formic acid in ACN, 20 mL / min, 70-75% ACN in H2O) and the product fraction was Lyophilised to give tert-butyl ((1r,4r)-4-(((4-((tert-butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 4-yl)amino)methyl)cyclohexyl)carbamate 2 (130 mg, 0.202 mmol, 43% yield) as off white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.19 (d, J = 7.20 Hz, 1H), 7.11 (d, J = 8.00 Hz, 1H), 6.78 (t, J = 5.20 Hz, 1H), 6.64 (d, J = 6.80 Hz, 1H), 5.17- 5.08 (m, 1H), 4.27 (d, J = 17.20 Hz, 1H), 4.38 (d, J = 16.80 Hz, 1H), 3.44 (s, 1H), 3.13 (dd, J = 6.80, 28.00 Hz, 4H), 2.89 (t, J = 6.00 Hz, 3H), 2.04 (q, J = 4.80 Hz, 1H), 1.52 (t, J = 21.20 Hz, 4H), 1.36 (d, J = 9.20 Hz, 28H). LCMS: 642.4 (M+H), Rt (min): 2.992, Area %: 99.757. HPLC: Rt (min): 4.691, Area %: 99.938.

[0370] Step-3: 3-(4-((4-aminobutyl)(((1s,4s)-4-aminocyclohexyl)methyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HClTo an ice cold solution of tert-butyl ((1s,4s)-4-(((4-((tert-butoxycarbonyl)amino)butyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamate (130 mg, 0.203 mmol, 1 equiv) in DCM (2.5 ml) was added HCl (4M in ethyl acetate, 1.3 mL, 5.20 mmol) at 0 °C and stirred for 2h at room temperature. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was concentrated, washed with MTBE (10 mL) and dried to get 3- (4-((4-aminobutyl)(((1s,4s)-4-aminocyclohexyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione, 2HCl 106 (85 mg, 0.165 mmol, 81 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 8.10 (d, J = 35.60 Hz, 5H), 7.43 (s, 1H), 7.26 (s, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.39 (q, J = 16.80 Hz, 2H), 3.16 (d, J = 26.00 Hz, 4H), 2.97- 2.88 (m, 1H), 2.76 (d, J = 4.80 Hz, 2H), 2.63 (s, 1H), 2.51 (t, J = 1.60 Hz, 1H), 2.05 (t, J = 5.20 Hz, 1H), 1.68 (s, 12H). LCMS: 442.4 (M+H), Method: Mobile phase: A: 0.1% TFA in H2O; Mobile phase: B: 0.1% TFA in ACN, Column: XBridge C8 (50 × 4.6 mm) 3.5 μm, Flow Rate: 1.5 ml / min, Rt (min): 1.027, Area %: 99.640. HPLC: Method:A: 0.1% TFA in H2O, B: ACN, Flow Rate: 2.0 ml / min, COLUMN: Xbridge C8(50 × 4.6) mm, 3.5 μm Rt (min): 1.655, Area %: 99.741.

[0371] Hydrochloride Salt Form of Compound 107

[0372] 3-(4-((4-aminobutyl)(((1r,4r)-4-aminocyclohexyl)methyl)amino)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione, HCl

[0373] Step-1: tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamate 2A To a cooled solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (500 mg, 2.180 mmol, 1 equiv) in DCM (11 ml) was added DMSO (3.7 ml), DIPEA (1.510 ml, 8.48 mmol, 3.89 equiv) followed by a solution of pyridine sulfur trioxide (1.35 g, 8.48 mmol, 3.89 equiv) in DMSO (3.7 ml) in drops. The mixture was stirred at 0 °C for 15 min. Upon completion of reaction (as confirmed by TLC (40% ethyl acetate in pet ether, Rf: 0.4), the reaction mixture was quenched with 1.5N HCl (20 mL) and extracted with DCM (2× 20 mL). The combined organic layer was concentrated under vacuum to give the crude product of tert-butyl ((1r,4r)-4- formylcyclohexyl)carbamate 2A (500 mg, 2.123 mmol, 97 % yield) as yellow solid1H-NMR (400 MHz, DMSO-d6): δ 9.55 (d, J = 0.80 Hz, 1H), 6.75 (d, J = 7.60 Hz, 1H), 3.16 (s, 1H), 2.52 (q, J = 2.00 Hz, 3H), 2.09 (d, J = 17.60 Hz, 2H), 1.92-1.83 (m, 5H), 1.38 (s, 1H), 1.19 (d, J = 8.80 Hz, 5H). LCMS: 172 (M-56), Rt (min): 2.587, Area %: 96.528.

[0374] Step-2: tert-butyl ((1r,4r)-4-(((4-((tert-butoxycarbonyl)amino)butyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamateTo a solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate Int4 (200 mg, 0.465 mmol, 1 equiv) and tert-butyl ((1r,4r)-4- formylcyclohexyl)carbamate 2A (528 mg, 2.323 mmol, 5 equiv) in DCE (2 ml) and DMF (0.5 ml) mixture was added TFA (47.7 mg, 0.418 mmol, 0.9 equiv) and Na(OAc)3BH (35.0 mg, 0.557 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 12 h. Upon completion of the reaction (as confirmed UPLC) the reaction mixture was quenched with ice water (25 mL) and extracted with DCM (2×10 ml). The combined organic layer was concentrated under vacuum to give crude. The crude product was purified by Isolera (column size: Biotage R snap cartridge, KP-Sil, 25 g, Silica gel 230-400 mesh) using 50-60 % ethyl acetate in pet ether to get tert-butyl ((1r,4r)-4-(((4-((tert-butoxycarbonyl)amino)butyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamate 2 (60 mg, 0.093 mmol, 19.97 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.18 (d, J = 7.20 Hz, 1H), 7.09 (d, J = 8.00 Hz, 1H), 6.78 (t, J = 5.60 Hz, 1H), 6.65 (d, J = 8.00 Hz, 1H), 5.13- 5.08 (m, 1H), 4.38 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 16.80 Hz, 1H), 4.03 (q, J = 7.20 Hz, 1H), 3.17 (d, J = 6.80 Hz, 3H), 3.03 (d, J = 6.80 Hz, 2H), 2.93-2.87 (m, 3H), 2.56 (t, J = 2.00 Hz, 2H), 2.02 (t, J = 9.20 Hz, 1H), 1.71 (d, J = 8.80 Hz, 4H), 1.36 (d, J = 2.00 Hz, 24H), 1.04-0.90 (m, 4H), LCMS: 642.4 (M+H), Rt (min): 2.900 min, Area %: 99.216. HPLC: Rt (min): 4.591, Area %: 97.770.

[0375] Step-3:3-(4-((4-aminobutyl)(((1r,4r)-4-aminocyclohexyl)methyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, HCl To an ice cold solution tert-butyl ((1r,4r)-4-(((4-((tert-butoxycarbonyl)amino)butyl)(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)cyclohexyl)carbamate 2 (60 mg, 0.093mmol,of 1 equiv) in DCM (1.7 mL), was added HCl (4 M soln. in ethyl acetate, 0.89 ml, 3.56 mmol, 5 vol) and stirred for 6 h at room temperature. Upon completion of the reaction (as confirmed by UPLC), the reaction mixture was concentrated, washed with MTBE (10 mL) to give the crude which was lyophilised to afford 3-(4-((4-aminobutyl)(((1r,4r)-4- aminocyclohexyl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl (35 mg, 0.072 mmol, 77 % yield) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.98 (t, J = 31.60 Hz, 6H), 7.40 (t, J = 7.60 Hz, 1H), 7.20 (t, J = 22.40 Hz, 2H), 5.12 (q, J = 5.20 Hz, 1H), 4.35 (q, J = 17.20 Hz, 2H), 3.20 (s, 2H), 3.06 (d, J = 6.40 Hz, 2H), 2.96-2.90 (m, 2H), 2.88-2.68 (m, 2H), 2.61 (d, J = 18.40 Hz, 2H), 2.04 (q, J = 5.20 Hz, 1H), 1.21 (q, J = 12.40 Hz, 2H), 0.98 (q, J = 12.40 Hz, 2H). LCMS: 441.0 (M-H), Method: Mobile phase: A: 0.1% FA in H2O; Mobile phase: B: ACN; Column: Atlantis dC18 (50 × 4.6 mm) 5 μm; Flow Rate: 1.5 ml / min; Rt (min): 0.995, Area %: 98.488. HPLC: Method: Mobile Phase A: 0.1% TFA in WATER; Mobile Phase B: Acetonitrile; Column: Atlantis dC18 (250 × 4.6) mm, 5 μm; Flow rate: 1.0 ml / min; Rt (min): 6.025, Area %: 97.654.

[0376] Hydrochloride Salt Form of Compounds 108 and 109

[0377] 3-(4-((4-Aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

[0378] Step-1: 3-(4-(((1s,4s)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione and 3-(4-(((1r,4r)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione To a stirred solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione 1 (3 g, 11.57 mmol, 1.0 equiv) in TFA (30 ml) was added sodium triacetoxyhydroborate (12.26 g, 57.9 mmol,5.0 equiv) and stirred at -15 °C for 10 min, then added 4-methylcyclohexan-1-one 2 (10.38 g, 93 mmol, 8.0 equiv) in DCM (10 ml), stirred the reaction for 16 h. The solvent was remove under reduced pressure to obtain crude. The crude compound was purified by reverse-phase coloumn chromatography (Grace® coloumn: C1840 µm, 350 g; flow rate: 60 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). Desired fraction was distilled under reduced pressure to obtain the cis and trans mixture 3-(4-((4-methylcyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (0.56 g, 13.62 % yield) as off-white solid. The Cis-trans mixture was sepearted by prep- HPLC (Column: X-Select-C18-19 x 250mm, Mobile phase: 0.1% TFA in Water / ACN, Flow- rate: 15 mL / min) to get 3-(4-(((1s,4s)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 108A (0.29 g, 7.05 % yield) as pale yellow solid and 3-(4-(((1r,4r)-4- methylcyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 109A (0.15 g, 3.65 % yield) as pale-yellow solid.

[0379] Step-2: tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)((1s,4s)-4-methylcyclohexyl)amino)butyl)carbamate To a stirred solution of 3-(4-(((1s,4s)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 108A (0.098 g, 0.276 mmol, 1.0 equiv) and tert-butyl (tert- butoxycarbonyl)(4-oxobutyl)carbamate (0.475 g, 1.654 mmol, 6.0 equiv) in DCM (5 ml) and DMF (2 ml) was added TFA (0.189 g, 1.654 mmol, 6.0 equiv) and sodium triacetoxyhydroborate (0.497 g, 2.344 mmol, 8.5 equiv) at 0 °C. The reaction mixture was warmed to RT and stirred for 16h. Upon completion of the reaction (as confirmed by UPLC), the reaction mixture was quenched by ice-water (50 mL) and extracted with DCM (2 × 30mL). The combined organic layer was dried with sodium sulphate, filterted and conentrated under reduced pressure to afford crude product. The crude product was purified by reverse-phase coloumn chromatography (Grace® coloumn: C1840 µm, 120 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACNmobile phase) to afford desired product tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)((1s,4s)-4-methylcyclohexyl)amino)butyl)carbamate (0.07 g, 39.7 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.42 (t, J = 7.60 Hz, 1H), 7.34-7.27 (m, 2H), 5.13-5.08 (m, 1H), 4.36-4.25 (m, 2H), 3.41-3.38 (m, 2H), 3.13-3.10 (m, 3H), 2.94-2.86 (m, 1H), 2.68-2.67 (m, 2H), 2.01-1.98 (m, 1H), 1.72-1.64 (m, 3H), 1.48-1.44 (m, 25H), 1.38-1.23 (m, 3H), 0.94-0.92 (m, 3H), LCMS: 627.4 (M+H), Rt (min): 3.41, Area% - 97.91. HPLC: Rt (min): 4.88, Area: 99.57%.

[0380] Step-3: 3-(4-((4-aminobutyl)((1s,4s)-4-methylcyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To an ice cold suspension of tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)((1s,4s)-4-methylcyclohexyl)amino)butyl)carbamate 5 (0.07 g, 0.112 mmol, 1.0 equiv) in DCM (3 ml) was added HCl (4M soln. EtOAc, 1 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated and washed with methyl tert- butyl ether (5 mL). The solvent was decanted and concentrated under reduced pressure to afford the crude product. The crude product was lyophilized to obtain 3-(4-((4- aminobutyl)((1s,4s)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl 108 (0.06 g, 106 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.81 (br s, 4H), 7.34-7.44 (m, 2H), 5.12 (t, J = 8.40 Hz, 1H), 4.31-4.35 (m, 2H), 3.13 (br s, 2H), 2.92 (s, 1H), 2.60-2.71 (m, 3H), 2.01-2.05 (m, 1H), 1.69-1.77 (m, 4H), 1.57-1.63 (m, 8H), 1.24-1.31 (m, 2H), 0.93-0.94 (m, 3H). LCMS: 427.3 (M+H). Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate:1.5 ml / min. COLUMN: XBridge C8 (50 × 4.6 mm) 3.5 μm. Rt (min): 1.340; Area% - 99.13.HPLC Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 2.0 mL / min. COLUMN: Xbridge C8(50 × 4.6) mm, 3.5 μm. Rt (min): 2.38; Area% - 98.95.

[0381] Step-2A: tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)((1r,4r)-4-methylcyclohexyl)amino)butyl)carbamate To a stirred solution of 3-(4-(((1r,4r)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, 109A (0.1 g, 0.281 mmol, 1.0 equiv) and tert-butyl (tert- butoxycarbonyl)(4-oxobutyl)carbamate (0.162 g, 0.563 mmol, 2.0 equiv) in DMF (5 ml): DCM (5 ml) was added TFA (0.160 g, 1.407 mmol, 4.0 equiv). After 10 minutes, sodium triacetoxyhydroborate (0.239 g, 1.125 mmol, 4.0 equiv) was added portionwise to this mixture at 0 °C. The reaction mixture was stirred for 4 hour at room temperature. The completion of reaction was monitored by UPLC, which indicate 39% of SM. The reaction mixture was cooled down at 0°C and added tert-butyl (tert-butoxycarbonyl)(4-oxobutyl)carbamate (0.485 g, 1.688 mmol, 6.0 equiv), followed by addtion of TFA (0.160 g, 1.407 mmol, 5.0 equiv). After 10 minutes, sodium triacetoxyhydroborate (0.507 g, 2.391 mmol, 8.5 equiv) was added and stirred the reaction mixture for 16 hour at room temperature. The completion of reaction was monitored by UPLC. The reaction mixture was quenched by ice-water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was dried with sodium sulphate, filterted and concentrated under redcued pressure to afford crude product. The crude compound was purifed by flash column chromatography (silica-gel, 230-400 mesh size) using ethyl acetate / pet ether (50%) as an eluent to obtain desired product as off-white solid. The product was repurified by reverse-phase column chromatography (Grace coloumn: C1840 µm, 50 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase) to afford tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)((1r,4r)-4-methylcyclohexyl)amino)butyl)carbamate 5A (0.04 g, 20.87 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.42-7.38 (m, 1H), 7.30-7.23 (m, 2H), 5.11- 5.07 (m, 1H), 4.34-4.23 (m, 2H), 3.12-3.11 (m, 2H), 2.86-3.01 (m, 2H), 2.65-2.70 (m, 1H), 2.01- 1.98 (m, 1H), 1.69-1.66 (m, 4H), 1.53-1.46 (m, 5H), 1.37 (s, 18H), 1.22-1.33 (m, 3H), 0.99-0.91 (m, 2H), 0.85-0.83 (m, 3H). LCMS: 627.3 (M-H), Rt (min): 2.27, Area% - 92.32.

[0382] Step-3A: 3-(4-((4-aminobutyl)((1r,4r)-4-methylcyclohexyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride To an ice cold solution of tert-butyl (tert-butoxycarbonyl)(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)((1r,4r)-4-methylcyclohexyl)amino)butyl)carbamate 5A (0.04 g, 0.064 mmol, 1.0 equiv) DCM (3 ml) was added HCl (4M soln. in EtOAc, 1mL) at 0 °C. stirred the reaction mixture for 2 hour at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc Rf~ 0.3, and LCMS). The reaction mixture was taken for vaccum distillation to get the crude product. The crude product was washed with MTBE (5 mL), decant the solvent dried it under reduced pressure and lyophilized to afford desired product 1093-(4- ((4-aminobutyl)((1r,4r)-4-methylcyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.03 g, 101 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.99 (brs, 3H), 7.37-7.51 (m, 3H), 5.10-5.15 (m, 1H), 4.44-4.63 (m, 2H), 3.30 (s, 2H), 3.01 (s, 3H), 2.92-2.98 (m, 2H), 2.60-2.78 (m, 3H), 2.45-2.50 (m, 1H), 2.06-2.08 (m, 1H), 1.66-1.67 (m, 4H). LCMS: 345.1 (M+H). Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate:1.5 ml / min. COLUMN: XBridge C8 (50 × 4.6 mm) 3.5 μm. Rt (min): 1.351; Area% - 99.19. HPLC Method: Mobile Phase A: 0.1% TFA in H2O. Mobile Phase B: Acetonitrile. Flow rate: 2.0 mL / min. COLUMN: Xbridge C8(50 × 4.6) mm, 3.5 μm. Rt (min): 2.418; Area% - 99.64.

[0383] Hydrochloride Salt Form of Compound 115 To a solution of compound 10 (120 mg, 0.2 mmol, 1.0 eq.) in DCM (6.0 mL) were added piperidine (338 mg, 4.0 mmol, 20.0 eq.). The mixture was stirred at room temperature for 17 hours. Then the reaction mixture was concentrated under reduced pressure and purified by P- HPLC (acetonitrile / H2O: 20%-45%) to afford compound 115 (11.4 mg, 13%) as white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 10) = 0.9 Rf (Compound 115) = 0.1 LCMS: Calcd. for [C21H26N4O3]+: 383, Found: 383.1H NMR (400 MHz, D2O): δ 7.72 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 5.06 (dd, J = 13.3, 4.9 Hz, 1H), 4.53 (q, J = 17.5 Hz, 2H), 4.27 (s, 2H), 3.60 (s, 2H), 3.50-3.35 (m, 2H), 2.97-2.62 (m, 2H), 2.47-2.30 (m, 1H), 2.25-2.10 (m, 1H), 1.37-1.20 (m, 2H), 1.13 (dd, J = 14.5, 7.2 Hz, 2H), 0.65 (t, J = 7.2 Hz, 3H).

[0384] Hydrochloride Salt Form of Compound 116To a solution of compound 4 (20 mg, 0.04 mmol, 1.0 eq.) in MeOH (1 mL) were added HCl (0.2 mL, 2 N, 0.4 mmol, 10.0 eq.). The mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was purified by Biotage (C18, acetonitrile / H2O: 30%-60%) to afford compound 116 (14.0 mg, 74%) as white solid. TLC: DCM / methanol = 10 / 1 Rf (Compound 4) = 0.5 Rf (Compound 116) = 0.1 LCMS: Calcd. for [C21H26N4O3]+: 383, Found: 383.1H NMR (400 MHz, D2O): δ 8.30-8.20 (m, 2H), 7.42-7.25 (m, 3H), 4.98 (d, J = 12.6 Hz, 1H), 4.38 (q, J = 17.2 Hz, 2H), 3.67 (s, 2H), 3.11-2.98 (m, 2H), 2.81-2.62 (m, 4H), 2.42-2.22 (m, 1H), 2.15-2.01 (m, 1H), 1.53 (s, 3H), 1.50-1.28 (m, 4H).

[0385] Hydrochloride Salt Form of Compound 123

[0386] 3-(4-((4-amino-3,3-dimethylbutyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride

[0387] Step-1: 4-Methoxy-2,2-dimethyl-4-oxobutanoic acid To an ice cold solution of 2,2-dimethylsuccinic acid 1 (100 g, 684 mmol, 1 equiv) in methanol (1500 mL, 15 vol), was added concentrated.H2SO4(10 mL) dropwise and stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 40% EtOAc in pet ether, Rf~ 0.5, KMnO4), the reaction mixture was concentrated under vacuum at 30°C. The resulted residue was poured into ice cold solution of sat. NaHCO3solution (1000 mL) and washed with EtOAc (2 × 500 mL). The separated aqueous layer was further acidified with aq. HCl (6N) till pH~2 and extracted with EtOAc (2 x 800 mL). The combined organic extracts were washed with brine (1 x 600 mL), dried over Na2SO4, filtered and concentrated to afford 4- Methoxy-2,2-dimethyl-4-oxobutanoic acid 2 (40 g, 235 mmol, 34.3 % yield) as colorless liquid.1H-NMR (400 MHz, DMSO-d6): δ 12.17 (s, 1H), 3.57 (s, 3H), 2.53 (s, 2H), 1.18 (s, 6H).

[0388] Step-2: Methyl 4-amino-3,3-dimethyl-4-oxobutanoate To an ice cold solution of 4-Methoxy-2,2-dimethyl-4-oxobutanoic acid 2 (25 g, 156 mmol, 1 equiv) in DCM (250 mL, 10 vol) was added thionyl chloride (111 g, 937 mmol, 6 equiv) dropwise and stirred for 3 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc in pet ether, Rf~ 0.4, as methyl ester), the reaction mixture was distilled under vacuum and dried completely under reduced pressure. The resulted acid chloride mixture was dissolved in THF (250 mL) and added dropwise to a pre- cooled solution of NH3(0.5M soln. in THF, 375 mL) at -78°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, 60% EtOAc in pet ether, Rf~ 0.2.), the reaction mixture was concentrated and resulted residue was poured into ice cold solution of sat. NaHCO3solution (500 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to afford methyl 4-amino-3,3- dimethyl-4-oxobutanoate 3 (8 g, 50.3 mmol, 32.2 % yield) as pale yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 6.75-7.07 (m, 2H), 3.54 (s, 3H), 2.51 (s, 2H), 1.15 (s, 6H)

[0389] Step-3: 4-Amino-3,3-dimethylbutan-1-ol A solution of Methyl 4-amino-3,3-dimethyl-4-oxobutanoate 3 (13 g, 82 mmol, 1 equiv) in THF (100 mL, 8 vol) was treated with LiAlH4(2M in THF, 82 mL, 163 mmol, 2 equiv) dropwise at 0 °C over a period of 30 minutes. Once the addition was complete, the reaction mixture was warmed to room temperature, slowly heated to 65°C and stirred for 2 h. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc, Rf~ 0.1), the reaction mixture was cooled to 0°C and slowly quenched with saturated Na2SO4solution (30 ml), precipitated inorganic salts were removed by filtration through Celite pad and washed with EtOAc (1 × 100 mL). The combined filtrate was dried over Na2SO4, filtered and concentrated to afford 4-amino-3,3-dimethylbutan-1-ol 4 (7.8 g, 64.0 mmol, 78 % yield) as a pale brown liquid, which was used without further purification.1H-NMR (400 MHz, DMSO-d6): δ 3.40-3.43 (m, 2H), 2.30 (s, 2H), 1.35-1.38 (m, 2H), 0.80 (s, 6H).

[0390] Step-4: tert-Butyl (4-hydroxy-2,2-dimethylbutyl)carbamate To a solution of 4-Amino-3,3-dimethylbutan-1-ol 4 (7.5 g, 57.2 mmol, 1 equiv) in THF (150 mL, 20 vol) and water (40 mL, 5 vol) were added sodium bicarbonate (7.2 g, 86 mmol, 1.5 equiv) and Boc2O (14 mL, 57.2 mmol, 1 equiv) in drops at room temperature. The resulted reaction mixture was stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc, Rf~ 0.7), the reaction mixture was diluted with EtOAc (1 × 100 mL), layer seperated, extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with brine solution (1 × 100 mL) and dried over Na2SO4and concentrated under reduced pressure to afford as a pale brown liquid. The resulted residue was purified by chromatography (column size: Biotage R snap cartridge, KP-Sil, 50 g, 100-200 silica gel) using 40-50% EtOAc in pet ether to afford tert-butyl (4-hydroxy-2,2-dimethylbutyl) carbamate 5 (5.0 g, 22.85 mmol, 40.0 % yield) as off-white crystalline solid.1H-NMR (400 MHz, DMSO-d6): δ 6.70 (s, 1H), 4.28 (t, J = 6.40 Hz, 1H), 3.41-3.47 (m, 2H), 2.76 (d, J = 8.80 Hz, 2H), 1.43 (s, 9H), 0.83 (s, 6H).

[0391] Step-5: tert-Butyl 2-hydroxy-4,4-dimethylpyrrolidine-1-carboxylate A solution of oxalyl chloride (0.5 mL, 5.52 mmol, 1.2 equiv) in DCM (5 mL) was added DMSO (1 mL, 14.08 mmol) dropwise at -78°C and stirred for 15 minutes at same temperature. To this, tert-Butyl (4-hydroxy-2,2-dimethylbutyl)carbamate (1.0 g, 4.6 mmol, 1 equiv) in DCM (3 mL) was added dropwise over a period of 15 minutes and stirred for 30 minutes at -78°C. At this point, N,N-Diisopropylethylamine (2.4 mL, 13.81 mmol, 3 equiv) was added dropwise to the mixture at -78°C and slowly warmed to 0 °C. After stirred for 30 minutes at 0°C, the reactioncompletion was confirmed by TLC analysis (20% EtOAc in pet ether, Rf~ 0.6, KMnO4). The reaction mixture was diluted with DCM (20 mL) and washed with 10% aq citric acid solution (1 × 50 mL), water (1 × 30 mL) and brine (1 × 30 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30°C to afford tert-Butyl 2-hydroxy-4,4-dimethylpyrrolidine- 1-carboxylate (0.95 g, crude) as pale yellow liquid which was used further without purification. GCMS: Mass found; MS: 215.1; Rt (min): 3.005. Method: HP5_SCAN350_MS.amx

[0392] Step-6: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)- 2,2-dimethylbutyl)carbamate To a stirred mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.86 mmol, 1.0 equiv) and tert-butyl 2-hydroxy-4,4-dimethylpyrrolidine-1-carboxylate (0.996 g, 4.63 mmol,1.2 equiv) in CH2Cl2(10 ml) and DMF (10.00 ml) was added trifluoroacetic acid (1.189 ml, 15.43 mmol, 4.0 equiv) and stirred for 10 min at 0 °C. To this mixture, sodium triacetoxyborohydride (3.27 g, 15.43 mmol, 4.0 equiv) was added in portions at 0°C and the resulted colourless cloudy mass was stirred for 16 hours at room temperature. Upon completion of the reaction (as confirmed by TLC and LCMS analysis, 100% EtOAc, Rf ~ 0.7), the reaction mixture was quenched with ice cold water (20 ml) and extarcted with dichloromethane (2 × 50 ml). The combined organic layer was dried over Na2SO4and concentrated under vaccum to afford crude as a pale yellow liquid. The crude compound was purified by Isolera chromatography (column size: Biotage R snap cartridge, KP-Sil, 100 g, 100-200 silica gel) using 75-85% of ethyl acetate in pet ether.The fractions were collected and contrated under vaccum to afford tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2,2- dimethylbutyl)carbamate 8 (0.6 g, 1.049 mmol, 27.2 % yield) as pale yellow semi solid.1H-NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 7.29 (t, J = 10.40 Hz, 1H), 6.93 (d, J = 10.00 Hz, 1H), 6.82-6.86 (m, 1H), 6.75 (d, J = 10.80 Hz, 1H), 5.49 (s, 1H), 5.08-5.15 (m, 1H), 4.08-4.25 (m, 2H), 3.13-3.14 (m, 2H), 2.73-2.91 (m, 3H), 2.65 (m, 1H), 2.30-2.36 (m, 1H), 2.01-2.08 (m, 1H), 1.45-1.50 (m, 2H), 1.38 (s, 9H), 0.94 (s, 6H). LC-MS: 403.1 (M-tBu), Rt (min): 2.302, Area% - 80.229.

[0393] Step-7: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)-2,2-dimethylbutyl)carbamate To a stirred mixture of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)- 2,2-dimethylbutyl)carbamate 8 (0.3 g, 0.654 mmol, 1.0 equiv) and pentanal 9 (0.564 g, 6.54 mmol, 10.0 equiv) in CH2Cl2(5 ml) and DMF (5.00 ml) was added trifluoroacetic acid (0.202 ml, 2.62 mmol, 4.0 equiv) and stirred for 10 min at 0 °C. Sodium triacetoxyborohydride (0.555 g, 2.62 mmol, 4.0 equiv) was added in portions at 0 °C and the resulted colourless cloudy mass was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC and LCMS analysis, 100% EtOAc, Rf ~ 0.8), the reaction mixture was quenched with ice cold water (20 ml) and extarcted with dichloromethane (2 × 50 ml). The combined organic layer was dried over Na2SO4and concentrated under vaccum to afford crude as a pale yellow liquid. The crude compound was purifed by prep-HPLC (Column: X-Bridge-c1819.1X250, Mobile phase: 0.1% FA in Water / ACN, FLOW rate:15 ml / min) to afford tert-butyl (4-((2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)-2,2-dimethylbutyl)carbamate 10 (80 mg, 0.145 mmol, 22.21 % yield) as a off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.34-7.39 (m, 1H), 7.16-7.18 (m, 1H), 6.82- 7.05 (m, 2H), 5.09-5.13 (m, 1H), 4.25-4.42 (m, 2H), 3.16-3.34 (m, 4H), 2.87-2.92 (m, 1H), 2.75- 2.77 (m, 3H), 2.02 (m, 1H), 1.36 (m, 9H), 1.25 (s, 9H), 0.80-0.83 (m, 9H). LCMS: 529.3 (M+H), Rt (min): 2.715, Area% - 99.791.

[0394] Step-8: 3-(4-((4-amino-3,3-dimethylbutyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochlorideTo a stirred suspension of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)-2,2-dimethylbutyl)carbamate 10 (80 mg, 0.151 mmol) in dichloromethane (2 mL) was added HCl (4M in ethylacetate, 5 ml, 165 mmol) at 0 °C and then stirred at room temperature for 16 h. Upon completion of the reaction (as confirmed by TLC analysis, 100%EtOAc, Rf ~ 0.1), the reaction mixture was concentrated under vaccum. The obtained solid was dissolved in water (10 mL) and washed with MTBE (10 mL), the water layer was lypholized to afford 3 afford 3-(4-((4-amino-3,3-dimethylbutyl)(pentyl)amino)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione, HCl 123 (70 mg, 0.145 mmol, 96 % yield) as a pale brown solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.87 (s, 3H), 7.16-7.43 (m, 3H), 5.11 (s, 1H), 4.33-4.35 (m, 2H), 3.22 (m, 4H), 2.90 (m, 1H), 2.63 (m, 3H), 2.50 (m, 3H), 2.10 (m, 1H), 1.43 (m, 3H), 1.24 (m, 4H), 0.94 (m, 5H), 0.83 (m, 3H) LCMS: 429.3 (M+H). Method: Column: X-BRIDGE C8 (50 × 4.6) 3.5 μm, Mobile phase: A: 0.1% TFA in H2O, B: 0.1% TFA in Acetonitrile, Flow Rate: 1.5 ml / min. HPLC: Method: Mobile phase: A: 10 mM Ammonium bicarbonate in water, Mobile phase: B: Acetonitrile, Flow: 1.0 mL / min, Column:X-Bridge C8(50 × 4.6) mm, 3.5 μm, RT: 5.333 min, Area: 96.027%.

[0395] Hydrochloride Salt Form of Compound 124

[0396] 3-(4-((4-amino-3,3-dimethylbutyl)(4-aminobutyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione dihydrochloride

[0397] Step-1: tert-butyl (4-((tert-butyldimethylsilyl)oxy)butyl)carbamate To a solution of tert-butyl (4-hydroxybutyl)carbamate (5.0 g, 26.4 mmol, 1.0 equiv)in dichloromethane (100 ml) was added imidazole (4.5 g, 66.0 mmol, 2.5 equiv) and TBS-Cl (4.78 g, 31.7 mmol, 1.5 equiv) at 0 °C and was allowed to stir at room temperature for 16 hours. Upon completion of the reaction (as confirmed by TLC, 20% EtOAc / pet ether, Rf~ 0.5, KMnO4). The reaction mixture was quenched with H2O (50 ml) and extracted with dichloromethane (1 × 50 mL). The organic layer was dried over Na2SO4and concentrated under vacuum to give crude compound. The crude compound was purified by chromatography (column size: Biotage R snap cartridge, KP-Sil, 100 g, 230-400 silica gel) using 10-15% EtOAc in pet-ether to afford tert-butyl (4-((tert-butyldimethylsilyl)oxy)butyl)carbamate (8.0 g, 26.3 mmol, 99% yield) as a colorless liquid.1H-NMR (400 MHz, DMSO-d6): δ 6.77 (s, 1H), 3.56 (t, 2H), 2.90 (t, 2H), 1.16-1.20 (m, 4H), 1.07 (s, 9H), 0.86 (s, 9H), 0.03 (s, 6H).

[0398] Step-2: tert-butyl (tert-butoxycarbonyl)(4-((tert- butyldimethylsilyl)oxy)butyl)carbamate n-BuLi (2.5 M soln. in hexane, 12.65 ml, 31.6 mmol, 1.2 equiv) was added to a stirred solution of tert-butyl (4-((tert-butyldimethylsilyl)oxy)butyl)carbamate 2 (8.0 g, 26.4 mmol, 1.0 equiv) in THF (80 ml)) at 0 °C and stirred for 15 min at 0 °C. A solution of (Boc)2O (7.34 ml, 31.6 mmol, 1.2 equiv) in THF (20 ml) was added to the reaction mixture at same temperature. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. Upon completion of the reaction (as confirmed by TLC analysis, 10% EtOAc / pet ether, Rf~ 0.7, KMnO4), the reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (2 × 100 ml). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford crude of tert-butyl (tert-butoxycarbonyl)(4-((tert-butyldimethylsilyl)oxy)butyl)carbamate 3 (11.0 g, 27.0 mmol, 102 % yield) as a pale yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 3.58 (t, 2H), 3.48 (t, 2H), 1.16-1.20 (m, 4H), 1.07 (s, 18H), 0.86 (s, 9H), 0.03 (s, 6H).

[0399] Step-3: tert-butyl (tert-butoxycarbonyl)(4-hydroxybutyl)carbamate To a stirred solution of the tert-butyl (tert-butoxycarbonyl)(4-((tert-butyldimethylsilyl) oxy)butyl)carbamate 3 (10 g, 24.77 mmol, 1.0 equiv) in THF (160 ml) at room temperature, was added TBAF (1M soln. in THF, 24.77 ml, 24.77 mmol, 1.5 equiv) and stirred at same temperature for over night. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc / pet ether, Rf~ 0.2, KMnO4). The reaction mixture was quenched with water (50 ml) and extracted with DCM (2 × 50 ml). The combined organic layer was dried over Na2SO4 and cocnentrated under reduced pressure to afford the crude as a dark yellow liquid. The crude compound was purified by Isolera chromatography (Biotage R snap cartridge, KP-Sil, 100 g,230-400 silica gel) using 15-20% EtOAc in pet-ether to afford tert-butyl (tert- butoxycarbonyl)(4-hydroxybutyl)carbamate 4 (6 g, 20.53 mmol, 83 % yield) as yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 4.40 (t, J = 6.80 Hz, 1H), 3.41-3.48 (m, 2H), 3.33-3.39 (m, 2H), 1.44 (m, 4H), 1.27 (s, 18H)

[0400] Step-4: tert-butyl (tert-butoxycarbonyl)(4-oxobutyl)carbamate A solution of oxalyl chloride (1.8 ml, 20.73 mmol, 2.0 equiv) and CH2Cl2(30 ml) was added DMSO (2.95 ml, 41.5 mmol, 4.0 equiv) in CH2Cl2(5 ml) at -78 °C and stirred for 15 minutes at same temperature. To this mixture, a solution of tert-butyl (tert-butoxycarbonyl)(4- hydroxybutyl)carbamate 4 (3 g, 10.37 mmol, 1.0 equiv) in CH2Cl2 (10 ml) was added at -78 °C. After stirring the reaction mixture for 30 minutes at -78 °C, triethylamine (9 ml, 62.2 mmol, 6.0 equivin drops at -78 °C. Then, the reaction mixture was slowly warmed to 0 °C and stirred for 30 min. Upon completion of the reaction (as confirmed by TLC analysis, 45% EtOAc / pet ether, Rf~ 0.6, KMnO4), the reaction mixture was diluted with DCM (20 mL) and washed with 10% aq citric acid solution (1 × 100 mL), and water (1 × 100 mL), dried over Na2SO4and concentrated under reduced pressure (below 30°C). The crude was codistilled with toluene to afford tert-butyl (tert-butoxycarbonyl)(4-oxobutyl)carbamate 5 (3.2 g, 11.14 mmol, 107 % yield) as yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 9.65 (s, 1H), 3.48 (t, J = 9.20 Hz, 2H), 2.41-2.50 (m, 2H), 1.70-2.30 (m, 2H), 1.44 (s, 18H),

[0401] Step-5: tert-butyl(tert-butoxycarbonyl)(4-((4-((tert-butoxycarbonyl)amino)-3,3- dimethylbutyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl) amino) butyl)carbamateTo a stirred mixture of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)- 2,2-dimethylbutyl)carbamate 8 (0.3 g, 0.654 mmol, 1.0 equiv) and tert-butyl (tert- butoxycarbonyl)(4-oxobutyl)carbamate 5 (0.376 g, 1.308 mmol, 2.0 equiv) in CH2Cl2(5 ml) and DMF (5.00 ml) was added trifluoroacetic acid (0.202 ml, 2.62 mmol, 4.0 equiv) and stirred for 10 min at 0 °C. To this mixture, sodium triacetoxyborohydride (0.555 g, 2.62 mmol, 4.0 equiv) was added in portions at 0°C and the resulted colourless cloudy mass was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100%EtOAc, Rf ~ 0.7), the reaction mixture was quenched with ice cold water (20 ml) and extarcted with DCM (2 × 50 ml). The combined organic layer was dried over Na2SO4and concentrated under vaccum to afford crude compound.The crude compound was purified by prep-HPLC purification (Column: X-Bridge-c1819.1 × 250, Mobile phase: 0.1% FA in Water / ACN, FLOW rate:15 ml / min), to afford tert-butyl (tert-butoxycarbonyl)(4-((4-((tert- butoxycarbonyl)amino)-3,3-dimethylbutyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 9 (75 mg, 0.100 mmol, 15.28 % yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.95 (s, 1H), 7.35-7.39 (m, 1H), 7.19-7.21 (m, 1H), 7.05- 7.07 (m, 1H), 6.79-6.81 (m, 1H), 5.10-5.14 (m, 1H), 4.26-4.41 (m, 2H), 3.43-3.46 (m, 2H), 3.17- 3.19 (m, 4H), 2.89-2.93 (m, 1H), 2.68-2.75 (m, 2H), 2.00-2.02 (m, 2H), 1.29-1.49 (m, 16H), 1.24 (s, 18H), 0.80 (s, 6H). LCMS: 730.4 (M+H). Method: Atlantis dC18 (50 × 4.6 mm) 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min. HPLC: Method: Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile, Flow rate: 2.0 ml / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. RT: 5.166 min, Area :97.332 %

[0402] Step-6: 3-(4-((4-amino-3,3-dimethylbutyl)(4-aminobutyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochlorideTo a stirred solution of tert-butyl (tert-butoxycarbonyl)(4-((4-((tert-butoxycarbonyl)amino)-3,3- dimethylbutyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)carbamate 9 (70 mg, 0.096 mmol, 1.0 equiv) in CH2Cl2(3 ml) was added HCl (4M soln. in dioxane, 5 ml) at 0 °C and then stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. Reaction mixture was concentrated under vaccum at below 40 ºC to afford pale yellow solid. The obtained solid was dissolved in water (10 ml) and washed with MTBE (2 x 10 ml), the water layer was lypholized to afford 3-(4-((4-amino-3,3-dimethylbutyl)(4-aminobutyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl 124 (40 mg, 0.077 mmol, 80 % yield) as a off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 7.93 (s, 6H), 7.34-7.44 (m, 1H), 7.16-7.28 (m, 2H), 5.11-5.16 (m, 1H), 4.30-4.45 (m, 2H), 3.23 (m, 4H), 2.90-2.98 (m, 1H), 2.76-2.77 (m, 2H), 2.64-2.68 (m, 3H), 2.02-2.05 (m, 1H), 1.52 (m, 7H), 0.95-0.96 (m, 6H), LCMS: 430.2 (M+H). Method:Column: Atlantis dC18 (50 × 4.6) mm, 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min. HPLC: Method: Mobile Phase: 0.1% TFA in water, Mobile Phase B: Acetonitrile, Flow rate: 2.0 ml / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. RT: 1.407 min, Area :96.954 %.

[0403] Hydrochloride Salt Form of Compound 125

[0404] 3-(4-((5-amino-3,3-dimethylpentyl)(4-aminobutyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione dihydrochloride

[0405] Step-1: 5-ethoxy-3,3-dimethyl-5-oxopentanoic acid To an ice cold solution of 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione 1 (10 g, 70.3 mmol, 1 equiv) in ethanol (50 mL, 5 vol), was added sodium ethoxide (0.479 g, 7.03 mmol, 0.1 equiv) dropwise and stirred for 16 h at 85 °C. Upon completion of the reaction (as confirmed by LCMS analysis), the reaction mixture was distilled under reduced pressure. The resulted residue was poured into ice cold solution of sat. NaHCO3solution (200 mL) and washed with EtOAc (2 × 50 mL). The separated aqueous layer was further acidified with aq. HCl (6N, 40 mL, pH~2) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to afford 5-ethoxy-3,3-dimethyl-5- oxopentanoic acid 2 (6 g, 31.9 mmol, 45.3 % yield) as colorless liquid.1H-NMR (400 MHz, DMSO-d6): δ 12.03 (s, 1H), 4.04 (q, J = 7.20 Hz, 2H), 2.37 (s, 2H), 2.29 (d, J = 7.20 Hz, 2H), 1.18 (t, J = 7.20 Hz, 3H), 1.05 (s, 6H).

[0406] Step-2: ethyl 5-amino-3,3-dimethyl-5-oxopentanoateTo an ice cold solution of 5-ethoxy-3,3-dimethyl-5-oxopentanoic acid 2 (6 g, 31.9 mmol, 1 equiv) in DCM (60 mL, 10 vol) was added thionyl chloride (15 ml, 206 mmol, 6 equiv) dropwise followed by catalytic amount of DMF (2 drops) and stirred for 3.5 hours at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 30 % EtOAc in pet ether, Rf~ 0.8, as methyl ester), the reaction mixture was distilled and dried under reduced pressure. The resulted acid chloride mixture was dissolved in THF (30 mL) and added dropwise to a pre- cooled solution of ammonia (0.5 M in THF, 90 ml, 4159 mmol) at -78°C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Upon completion of the reaction (as confirmed by TLC analysis, 30% EtOAc in pet ether, Rf~ 0.2.), the reaction mixture was concentrated and resulted residue was poured into ice cold solution of sat. NaHCO3solution (150 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to afford ethyl 5-amino-3,3-dimethyl-5- oxopentanoate 3 (4.4 g, 159 mmol, 50% yield) as yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 7.21 (s, 1H), 6.73 (s, 1H), 4.04 (q, J = 7.20 Hz, 2H), 2.36 (s, 2H), 2.08 (s, 2H), 1.18 (t, J = 7.20 Hz, 3H), 1.03 (s, 6H). LCMS: 188.1 (M+H), Rt (min): 1.694, Area%: 99.678.

[0407] Step-3: 5-amino-3,3-dimethylpentan-1-ol A solution of ethyl 5-amino-3,3-dimethyl-5-oxopentanoate 3 (4.4 g, 23.50 mmol, 1 equiv) in THF (15 mL, 8 vol) was treated with LAH (2M in THF, 23.50 ml, 47.0 mmol, 2 equiv) dropwise at 0°C over a period of 5 minutes. Once the addition was complete, the reaction mixture was warmed to room temperature, then slowly heated to 65°C and stirred for 2 hours. Upon completion of the reaction (as confirmed by TLC analysis, EtOAc, Rf~ 0.2), the reaction mixture was cooled to 0°C and slowly quenched with saturated Na2SO4solution (60 ml), precipitated salts were removed by filtration through Celite pad and washed with EtOAc (50 mL). Thecombined filtrate was dried over Na2SO4, filtered and concentrated to afford 5-amino-3,3- dimethylpentan-1-ol 4 (2 g, 13.30 mmol, 56.6 % yield) as brown liquid.1H-NMR (400 MHz, CDCl3): δ 3.70 (t, J = 7.60 Hz, 3H), 2.73 (q, J = 8.00 Hz, 2H), 1.54 (t, J = 7.60 Hz, 2H), 1.44-1.40 (m, 2H), 1.02 (s, 1H), 0.93 (s, 9H). LCMS: 132.2 (M+H), Rt (min): 0.603, Area%: 87.229.

[0408] Step-4: tert-butyl (5-hydroxy-3,3-dimethylpentyl)carbamate To a stirred suspension of 5-amino-3,3-dimethylpentan-1-ol 4 (2 g, 15.24 mmol, 1 equiv) and sodium bicarbonate (2.56 g, 30.5 mmol, 2 equiv) in mixture of THF (30 mL, 15 vol) and water (2 mL, 1 vol) was added Boc-anhydride (3.54 ml, 15.24 mmol, 1 equiv) in dropwise at room temperature. The resulted reaction mixture was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by LCMS analysis), anhyd. Na2SO4was added to the reaction mixture, filtered and washed with EtOAc (20 mL). The resulted filtrate was concentrated under reduced pressure to give crude product as yellow liquid. The crude product was purified by column chromatography (Biotage R snap cartridge, KP-Sil, 100 g, 100-200 silica gel) using 20-25 % EtOAc in pet ether to afford tert-butyl (5-hydroxy-3,3- dimethylpentyl)carbamate 5 (1.7g, 7.33 mmol, 48.1 % yield) as yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 6.70 (s, 1H), 3.43 (d, J = 4.40 Hz, 2H), 2.94-2.87 (m, 2H), 1.44-1.20 (m, 16H), 0.78 (s, 6H). LCMS: 132.3 (M-Boc), Rt (min): 2.14, Area%: 99.812.

[0409] Step-5: tert-butyl (5-((tert-butyldimethylsilyl)oxy)-3,3-dimethylpentyl)carbamate To a solution of tert-butyl (5-hydroxy-3,3-dimethylpentyl)carbamate 5 (1.7 g, 7.35 mmol, 1.0 equiv) and imidazole (1.251 g, 18.37 mmol, 2.5 equiv) in DCM (20 ml) was added TBS-Cl (1.329 g, 8.82 mmol, 1.2 equiv) at 0 °C and was allowed to stir at room temperature for 13 h. Upon completion of the reaction (as confirmed by TLC, 30 % EtOAc in pet ether, Rf~ 0.9, KMnO4). The reaction was quenched with water (50 m1) and extracted with DCM (1 x 30 mL). The combined organic layer was dried over Na2SO4and cocnentrated under reduced pressure toafford tert-butyl (5-((tert-butyldimethylsilyl)oxy)-3,3-dimethylpentyl)carbamate 6 (2.5 g, 7.22 mmol, 98 % yield) as yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 6.69 (t, J = 5.20 Hz, 1H), 3.63 (t, J = 7.60 Hz, 2H), 2.90 (q, J = 5.60 Hz, 2H), 1.40 (s, 10H), 1.37 (s, 2H), 0.85 (t, J = 3.20 Hz, 14H), 0.03 (q, J = 2.80 Hz, 6H). LCMS: 246.2 (M-Boc), Rt (min): 3.581, Area%: 99.821.

[0410] Step-6: tert-butyl (tert-butoxycarbonyl)(5-((tert-butyldimethylsilyl)oxy)-3,3- dimethylpentyl)carbamate To a solution of tert-butyl (5-((tert-butyldimethylsilyl)oxy)-3,3-dimethylpentyl)carbamate 6 (2.5 g, 7.23 mmol) in THF (25 mL, 10 vol) was added n-BuLi (2.5 M in hexane, 3.47 ml, 8.68 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred for 15min at 0 °C. A solution of (Boc)2O (1.316 ml, 5.67 mmol, 1.2 equiv) in THF (10 mL) was added to the reaction mixture at same temperature. The resulting reaction mixture was warmed to room temperature and stirred for 1 hour. Upon completion of the reaction (as confirmed by TLC analysis, 5 % EtOAc in pet ether, Rf~ 0.8, KMnO4). The reaction mixture was quenched with water (50 ml) and extracted with DCM (2 × 30ml). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford tert-butyl (tert-butoxycarbonyl)(5-((tert-butyldimethylsilyl)oxy)-3,3- dimethylpentyl)carbamate 7 (3.5 g, 7.75 mmol, 107 % yield) as yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 1.47 (s, 9H), 1.44-1.41 (m, 4H), 0.91 (s, 4H), 0.86 (t, J = 4.40 Hz, 6H), 0.03 (d, J = 4.80 Hz, 3H). LCMS: 246.3 (M-200), Rt (min): 4.602, Area%: 98.718.

[0411] Step-7: tert-butyl (tert-butoxycarbonyl)(5-hydroxy-3,3-dimethylpentyl)carbamate To a solution of tert-butyl-(tert-butoxycarbonyl)(5-((tert-butyldimethylsilyl)oxy)-3,3- dimethylpentyl)carbamate 7 (3.5 g, 7.85 mmol) in THF (35 mL, 10 vol) was added TBAF (11.78 ml, 1M soln. in THF, 11.78 mmol, 1.5 equiv) and stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 30% EtOAc in pet ether, Rf~ 0.2,KMnO4). The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (2 × 30ml). The combined organic layer was dried over Na2SO4and cocnentrated under reduced pressure to afford the crude as yellow liquid. The crude compound was purified by column chromatography (Biotage R snap cartridge, KP-Sil, 50 g, 60-120 silica gel) using 12-15 % EtOAc in pet-ether to afford tert-butyl (tert-butoxycarbonyl)(5-hydroxy-3,3- dimethylpentyl)carbamate 8 (1.4 g, 4.22 mmol, 53.8 % yield) as pale yellow liquid.1H-NMR (400 MHz, DMSO-d6): δ 4.26 (t, J = 4.80 Hz, 1H), 3.50-3.44 (m, 4H), 1.45 (s, 16H), 1.38 (q, J = 7.60 Hz, 5H), 0.88 (s, 6H).

[0412] Step-8: tert-butyl (tert-butoxycarbonyl)(3,3-dimethyl-5-oxopentyl)carbamate A solution of oxalyl chloride 8 (0.317 ml, 3.62 mmol, 1.2 equiv) in DCM (10 mL) was added dropwise to a solution of DMSO (0.514 ml, 7.24 mmol, 2.4 equiv) at -78°C under nitrogen atmosphere and stirred for 15 minutes at the same temperature. To this, a solution of tert-butyl (tert-butoxycarbonyl)(5-hydroxy-3,3-dimethylpentyl)carbamate (1 g, 3.02 mmol, 1 equiv) in DCM (10 mL) was added dropwise over a period of 5 minutes. After stirring the reaction mixture for 30 minutes at -78 °C, was added TEA (2.103 ml, 15.09 mmol, 5 equiv) in drops at - 78 °C. Once addition was complete, the reaction mixture was slowly warmed to 0 °C. Upon completion of the reaction (as confirmed by TLC analysis, 30 % EtOAc in pet ether, Rf~ 0.8, KMnO4), the reaction mixture was diluted with DCM (10 mL) and washed with 10% aq citric acid solution (50 mL), water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum below 30°C to afford tert-butyl (tert-butoxycarbonyl)(3,3-dimethyl- 5-oxopentyl)carbamate 9 (930 mg, 2.82 mmol, 94 % yield) as yellow liquid which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 9.76 (q, J = 2.40 Hz, 1H), 3.49-3.44 (m, 2H), 2.29 (d, J = 2.80 Hz, 1H), 1.52 (d, J = 8.00 Hz, 1H), 1.49 (s, 12H), 1.44 (s, 1H), 1.02 (s, 3H), 0.88 (s, 1H).

[0413] Step-9: tert-butyl (tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,3- dimethylpentyl)carbamateTo a solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate Int-4 (1 g, 2.323 mmol), tert-butyl (tert-butoxycarbonyl)(3,3- dimethyl-5-oxopentyl)carbamate 9 (930 mg, 2.82 mmol, 1.2 equiv) and TFA (0.716 ml, 9.29 mmol, 4 equiv) in a mixture of Dichloromethane (10 mL, 10 vol) and DMF (10 mL, 10 vol) was added sodium triacetoxyborohydride (1.969 g, 9.29 mmol, 4 equiv) and stirred for 16 h at room temperature. TLC analysis (EtOAc, Rf~ 0.7) and LCMS indicated product formation and the starting material was not consumed completely. The reaction mixture was diluted with DCM (15 mL) and washed with water (2 × 30mL), brine (30 mL), dried over anhy. Na2SO4, filtered and concentrated. The resulted residue was purified by prep.HPLC (HCOOH:ACN method) and lyophilized to get tert-butyl (tert-butoxycarbonyl)(5-((4-((tert-butoxycarbonyl)amino)butyl)(2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,3-dimethylpentyl)carbamate 10 (70 mg, 0.094 mmol, 4.04 % yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.38 (t, J = 7.60 Hz, 1H), 7.19 (d, J = 7.20 Hz, 1H), 7.08 (d, J = 7.60 Hz, 1H), 6.77 (s, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.40 (d, J = 16.80 Hz, 1H), 4.29 (d, J = 17.20 Hz, 1H), 3.46 (t, J = 9.20 Hz, 2H), 3.25 (d, J = 28.00 Hz, 4H), 2.93 (t, J = 7.20 Hz, 3H), 2.04 (t, J = 7.60 Hz, 1H), 1.44 (t, J = 8.40 Hz, 20H), 1.37 (d, J = 14.00 Hz, 12H), 1.02 (s, 6H). LC-MS: 744.5 (M+H), Rt (min): 3.010, Area%: 99.774.

[0414] Step-10: 3-(4-((5-amino-3,3-dimethylpentyl)(4-aminobutyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochlorideTo a stirred suspension of tert-butyl (tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,3- dimethylpentyl)carbamate 10 (70 mg, 0.094 mmol) in dichloromethane (3 mL) was added HCl (4M soln. in dioxane, 1 ml, 4.00 mmol) at 0 °C and then stirred at room temperature for 2 h. Upon completion of the reaction (as confirmed by TLC analysis, EtOAc, Rf ~ 0.1), the reaction mixture was concentrated under reduced pressure. The obtained solid was dissolved in water (30 mL) and washed with MTBE (2 × 30 mL), the water layer was lypholized to afford 3-(4-((5- amino-3,3-dimethylpentyl)(4-aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl 125 (12 mg, 0.023 mmol, 24.65 % yield) as off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.00 (s, 6H), 7.54 (s, 2H), 5.17-5.12 (m, 1H), 4.49 (d, J = 31.20 Hz, 2H), 3.35 (s, 4H), 2.92 (d, J = 12.40 Hz, 1H), 2.75-2.61 (m, 5H), 2.07 (t, J = 5.20 Hz, 1H), 1.51 (q, J = 8.40 Hz, 6H), 1.39-1.30 (m, 2H), 0.87 (s, 6H). LCMS: 444.3 (M+H). Method: Mobile Phase A: 0.1% Formic acid in H2O. Mobile Phase B: ACN. Flow rate:1.5 ml / min. Column: Atlantis dC18 (50 x4 .6) 5 μm. Rt (min): 1.035; Area%: 99.826. HPLC: Method: Mobile Phase A: 0.1% Formic acid in H2O. Mobile Phase B: Methanol. Flow rate: 1.0 mL / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. Rt (min): 2.679; Area%: 98.409.

[0415] Hydrochloride Salt Form of Compound 126

[0416] 3-(4-((5-amino-4,4-dimethylpentyl)(4-aminobutyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione dihydrochloride

[0417] Step-1: 5-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpentanenitrile To a solution of LDA (2M in THF / Heptane / Ethyl benzene, 5.92 ml, 11.85 mmol, 1.5 equiv) in THF (10 ml) was cooled to -78 °C and added isobutyronitrile 2 (0.764 g, 11.06 mmol, 1.4 equiv) over 5 minutes. The reaction mixture was allowed to warm to -40°C and stirred for 30 min. and again cooled to -78°C. Then (3-bromopropoxy)(tert-butyl)dimethylsilane 1 (2.0 g, 7.90 mmol, 1.0 equiv) was added dropwise to the reaction mixture and was allowed to warm to 0°C and stirred for 1 h. Upon completion of the reaction (as confirmed by TLC and UPLC analysis, 10% EtOAc / pet ether, Rf ~ 0.6, KMnO4), the reaction mixture was quenched with 1 N HCl (1 x 10 ml) and extracted with MTBE (2 × 50 ml). The combined organic layer was washed saturated NaHCO3(1 x 20 ml), brine (1 x 20 ml) and dried over Na2SO4and concentrated under reducedpressure to afford 5-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpentanenitrile 3 (2.2 g, 9.11 mmol, 115% yield) as a pale yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 3.66-3.69 (m, 2H), 1.69-1.73 (m, 2H), 1.59-1.63 (m, 2H), 1.38 (s, 6H), 0.91 (s, 9H), 0.08 (s, 6H)

[0418] Step-2: tert-butyl (5-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpentyl)carbamate To a stirred solution of 5-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpentanenitrile 3 (1.0 g, 4.14 mmol, 1.0 equiv) in dry MeOH (30 ml), cooled to 0 °C, were added (Boc)2O (1.923 ml, 8.28 mmol, 2.0 equiv), NiCl2.6H2O (0.984 g, 4.14 mmol, 1.0 equiv) and NaBH4(1.097 g, 29.0 mmol, 7.0 equiv) was then carefully added in small portions. The reaction was exothermic and effervescent. The resulting reaction mixture was allowed to warm to room temperature and stirred for over night. Upon completion of the reaction (as confirmed by TLC analysis, 5% EtOAc / pet ether, Rf ~ 0.3, KMnO4), the reaction mixture was diluted with DCM (20 ml) and filtered through celite bed and washed with DCM (20 ml). The filtrate was washed with saturated NaHCO3solution (1 x 20 ml), the organic layer was dried over Na2SO4and cocentrated under reduced pressure to afford crude of tert-butyl (5-((tert-butyldimethylsilyl)oxy)-2,2- dimethylpentyl)carbamate 4 (1.2 g, 3.39 mmol, 82 % yield) as a pale yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 6.71 (t, J = 6.40 Hz, 1H), 3.54 (m, 2H), 2.73-2.76 (m, 2H),1.44 (s, 9H), 1.22-1.38 (m, 2H), 1.07-1.13 (m, 2H), 0.89 (s, 9H), 0.80 (s, 6H), 0.02 (s, 6H).

[0419] Step-3: tert-butyl(tert-butoxycarbonyl)(5-((tert-butyldimethylsilyl)oxy)-2,2- dimethylpentyl) carbamate To a stirred solution of tert-butyl (5-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpentyl)carbamate 4 (2.5 g, 7.23 mmol, 1.0 equiv) in THF (50 mL) at 0 °C, was added n-BuLi (2.5 M soln. in hexane, 3.47 ml, 8.68 mmol, 1.2 equiv). The reaction mixture was stirred for 15 min at 0 °C. A solution of (Boc)2O (2.015 ml, 8.68 mmol, 1.2 equiv) in THF (10 mL) was added to the reaction mixture at same temperature. The resulting reaction mixture was warmed to room temperature and stirred for 1 h. Upon completion of the reaction (as confirmed by TLC analysis, 10%EtOAc / pet ether, Rf~ 0.7, KMnO4), the reaction mixture was quenched with water (50 ml) and extracted with DCM (2 × 100 ml). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford tert-butyl (tert-butoxycarbonyl)(5-((tert- butyldimethylsilyl)oxy)-2,2-dimethylpentyl)carbamate 5 (3.2 g, 6.82 mmol, 94 % yield). as a pale yellow liquid, which was used further without purification1H-NMR (400 MHz, DMSO-d6): δ 3.59-3.54 (m, 2H), 2.73-2.76 (m, 2H), 1.42 (s, 18H), 1.24- 1.36 (m, 2H), 1.07-1.13 (m, 2H), 0.89 (s, 9H), 0.80 (s, 6H), 0.02 (s, 6H).

[0420] Step-4: tert-butyl (tert-butoxycarbonyl)(5-hydroxy-2,2-dimethylpentyl)carbamate To a stirred solution of the tert-butyl (tert-butoxycarbonyl)(5-((tert-butyldimethylsilyl)oxy)-2,2- dimethylpentyl)carbamate (3.2 g, 7.18 mmol, 1.0 equiv) in THF (60 ml) at room temperature was added TBAF (1M soln. in THF, 10.8 ml, 10.8 mmol, 1.5 equiv) and the resulting solution was stirred at room temperature for over night. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc / pet ether, Rf~ 0.2, KMnO4), the reaction mixture was quenched with water (20 ml) and extracted with DCM (2 × 50 ml). The combined organic layer was dried over Na2SO4and cocnentrated under reduced pressure to afford the crude product as a dark yellow liquid. The crude compound was purified by Isolera (Biotage R snap cartridge, KP-Sil, 100 g, 100-200 silica gel) using 15-20% EtOAc in pet-ether. The fractions were collected and concentrated under vaccum to afford tert-butyl (tert-butoxycarbonyl)(5-hydroxy-2,2- dimethylpentyl)carbamate 6 (1.6 g, 4.82 mmol, 67.1 % yield) as a colorless liquid1H-NMR (400 MHz, DMSO-d6): δ 4.35 (t, J = 5.20 Hz, 1H), 3.36-3.39 (m, 2H), 3.32-3.35 (m, 2H), 1.47 (s, 18H), 1.36-1.40 (m, 2H), 1.12-1.16 (m, 2H), 0.79 (s, 6H).

[0421] Step-5: tert-butyl (tert-butoxycarbonyl)(5-oxopentyl)carbamate A solution of oxalyl chloride (0.845 ml, 9.65 mmol, 2.0 equiv) and CH2Cl2(20 ml) was added DMSO (1.370 ml, 19.31 mmol, 4.0 equiv) in CH2Cl2(5 ml) at -78 °C and stirred for 15 minutes at same temperature. To this mixture, a solution of tert-butyl (tert-butoxycarbonyl)(5-hydroxy- 2,2-dimethylpentyl)carbamate 6 (1.6 g, 4.83 mmol, 1.0 equiv) in CH2Cl2(5 ml) was added at -78 °C. After stirring the reaction mixture for 30 minutes at -78 °C, triethylamine (4.04 ml, 29.0mmol, 6.0 equiv) was added in drops at -78 °C. Then, the reaction mixture was slowly warmed to 0 °C and stirred for 30 min. Upon completion of the reaction (as confirmed by TLC analysis, 20% EtOAc / pet ether, Rf~ 0.6, KMnO4), the reaction mixture was diluted with DCM (40 mL) and washed with 10% aq citric acid solution (1 x 40 mL), water (1 x 40 mL), dried over Na2SO4, and concentrated under vacuum (below 30°C) to afford tert-butyl (tert-butoxycarbonyl)(2,2- dimethyl-5-oxopentyl)carbamate 7 (1.55 g, 3.42 mmol, 70.8 % yield) as a pale yellow liquid, which was used further without purification.1H-NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 3.39 (s, 2H), 2.42-2.50 (m, 2H), 1.44 (m, 2H), 1.42 (s, 18H), 0.79 (s, 6H)

[0422] Step-6: tert-butyl (tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2,2- dimethylpentyl)carbamate To a stirred mixture of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)butyl)carbamate 8 (0.5 g, 1.161 mmol, 1.0 equiv) and tert-butyl (tert- butoxycarbonyl)(2,2-dimethyl-5-oxopentyl)carbamate 7 (0.765 g, 2.323 mmol, 2.0 equiv) in CH2Cl2(10 ml) and DMF (10 ml) was added trifluoroacetic acid (0.358 ml, 4.65 mmol, 4.0 equiv) and stirred for 10 min at 0 °C. To this mixture, sodium triacetoxyborohydride (0.985 g, 4.65 mmol, 4.0 equiv) was added in portions at 0°C and the resulted colourless cloudy mass was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by TLC analysis, 100% EtOAc, Rf ~ 0.7), the reaction mixture was quenched with ice cold water (1 x 20 mL) and extarcted with DCM (2 × 50 mL). The combined organic layer was dried over Na2SO4and concentrated under vaccum to afford crude as a pale yellow liquid. The crude compound was purified by Isolera chromatography (column size: Biotage R snap cartridge, KP-Sil, 100 g, 230-400 silica gel) using 60-70 % of ethyl acetate in pet ether.The fractions were collected and concentrated under vaccum to afford tert-butyl (tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2,2- dimethylpentyl)carbamate 9 (0.25 g, 0.335 mmol, 28.9 % yield) as a white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.35-7.39 (m, 1H), 7.06-7.19 (m, 2H), 6.77- 6.79 (m, 1H), 5.09-5.13 (m, 1H), 4.27-4.42 (m, 2H), 3.10-3.21 (m, 4H), 2.89-2.90 (m, 4H), 2.67- 2.68 (m, 6H), 1.44 (s, 18H), 1.43 (m, 4H), 1.35 (s, 9H), 1.24 (m, 2H), 0.75 (s, 6H), LCMS: 744.5 (M+H). Method: Atlantis dC18 (50 × 4.6 mm) 5 μm, Mobile phase : A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min HPLC: Method: Mobile Phase A: 0.1% FA in water, Mobile Phase B: Acetonitrile, Flow rate: 2.0 ml / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. RT: 6.191 min, Area :96.037 %

[0423] Step-7: 3-(4-((5-amino-4,4-dimethylpentyl)(4-aminobutyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione dihydrochloride To a stirred solution of tert-butyl (tert-butoxycarbonyl)(5-((4-((tert- butoxycarbonyl)amino)butyl)(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2,2- dimethylpentyl)carbamate 9 (0.15 g, 0.202 mmol, 1.0 equiv) in dichloromethane (10 ml) was added HCl (4M soln. in dioxane, 10 ml) at 0 °C and then stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. Reaction mixture was concentrated under vaccum at below 40 ºC, to afford pale yellow solid. The obtained solid was dissolved in water (10 ml) and washed with MTBE (1 x 10 ml), the water layer was lypholized to afford 3-(4-((5- amino-4,4-dimethylpentyl)(4-aminobutyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, 2HCl (80 mg, 0.148 mmol, 73.4 % yield) as a pale yellow solid1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.94 (s, 6H), 7.43 (m, 1H), 7.25-7.28 (m, 2H), 5.11-5.15 (m, 1H), 4.12-4.50 (m, 2H), 3.20-3.26 (m, 4H), 2.90-2.98 (m, 1H), 2.76-2.89 (m,2H), 2.64-2.68 (m, 3H), 2.02-2.05 (m, 1H), 1.54 (m, 4H), 1.39 (m, 2H), 1.24-1.26 (m, 3H), 0.93 (s, 6H), LCMS: 444.4 (M+H). Method: Column: Atlantis dC18 (50 × 4.6 mm) 5 μm, Mobile phase: A: 0.1% FA in H2O, Mobile phase: B: Acetonitrile, Flow Rate: 1.5 ml / min. HPLC: Method: Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Methanol, Flow rate:1.0 ml / min. Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm. RT: 3.466 min, Area :95.684 %.

[0424] Compound 143

[0425] 1-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)butyl)-3- methylurea To a solution of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione,HCl (200 mg, 0.499 mmol, 1 equiv) and N-methyl-1H-imidazole-1-carboxamide (62.5 mg, 0.499 mmol, 1equiv) in DCM (4 ml) was added TEA (0.077 ml, 0.549 mmol, 1.1 equiv) and the resulting reaction mixture was stirred for 12h at room temperature. Upon completion of the reaction (as confirmed by UPLC), the reaction mixture was concentrated under vacuum to give the crude product which was purified by preparatory HPLC (Column: XBridge C8 - 150; Method: HCl and ACN, flow rate: 20ml / min) to give 1-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)(pentyl)amino)butyl)-3-methylurea (45 mg, 0.098 mmol, 19.56% yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.61 (s, 2H), 5.13 (q, J = 4.80 Hz, 1H), 4.74 (s, 2H), 2.96-2.88 (m, 3H), 2.65 (q, J = 17.60 Hz, 1H), 2.43 (q, J = 4.00 Hz, 1H), 2.08 (t, J = 5.60 Hz, 1H), 1.37 (t, J = 6.00 Hz, 5H), 1.22 (d, J = 2.80 Hz, 5H), 0.81 (t, J = 6.80 Hz, 3H). LCMS: 458.9 (M+H), Method: Mobile phase: A: 0.1% Formic Acid in H2O B: ACN; Column: Atlantis dC18 (50×4.6) 5 μ; Flow Rate: 1.5 ml / min; Rt (min): 1.830, Area%: 99.292.HPLC: Method: Mobile phase: A: 0.1% FA in water, Mobile phase D: ACN; Column: XBridge C8(50×4.6) mm, 3.5 μm, Flow rate:2.0 ml / min; Rt (min): 2.870, Area%: 99.180.

[0426] Compound 148

[0427] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)butyl)butyramide To a stirred solution of butyric acid 148a (0.150 g, 0.375 mmol, 1 equiv) in DMF (2 mL) were added DIPEA (0.262 ml, 1.498 mmol, 4 equiv) and HATU (0.214 g, 0.562 mmol, 1.5 equiv) at 0 °C. 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl 47 (0.150 g, 0.375 mmol, 1 equiv) was then added at same temperature and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as monitored by LCMS), reaction mixture was purified by prep-HPLC (Instrument: SC-DC-ARD-05-044; FLOW:15 ml / min; Coloumn: X-Select-C18-19x150mm; Mobile phase combination: 0.1% FA in Water / MeOH). The pure fractions were lyophilized to afford N-(4-((2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)(pentyl)amino)butyl)butyramide 148 (37.43 mg, 0.079 mmol, 20.99 % yield) as off white solid. LCMS: 471.2 (M+H). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% Formic Acid in H2O B: ACN, Flow Rate: 1.5 ml / min. Rt (min): 2.127; Area% - 99.68. HPLC: 98.85 %, Rt (min): 3.792. Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, Mobile phase: A: 0.1% FA in water, Mobile phase: B: ACN, Flow: 2.0 mL / min.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.71 (d, J = 5.20 Hz, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.19 (d, J = 7.20 Hz, 1H), 7.07 (d, J = 8.00 Hz, 1H), 5.10 (q, J = 4.80 Hz, 1H), 4.34 (dd, J = 16.80, 43.20 Hz, 2H), 3.17 (t, J = 7.20 Hz, 4H), 3.02 (d, J = 6.00 Hz, 2H), 2.91 (t, J = 12.80Hz, 1H), 2.68 (s, 1H), 2.62 (s, 1H), 1.99 (t, J = 7.20 Hz, 3H), 1.48-1.41 (m, 8H), 1.25 (d, J = 3.20 Hz, 4H), 0.86-0.80 (m, 6H).

[0428] Compound 149

[0429] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)butyl)-3- methylbutanamide To a stirred solution of 3-methylbutanoic acid 149a (35.1 mg, 0.343 mmol, 1 equiv) in DMF (3 ml) were added HATU (196 mg, 0.515 mmol, 1.5 equiv) and DIPEA (177 mg, 1.373 mmol, 4 equiv) at 0 °C, followed by addition of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, HCl 47 (150 mg, 0.343 mmol, 1 equiv) and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as monitored by UPLC), reaction mixture was purified by reverse-phase column chromatography (Grace column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions were lyophilised to afford N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl) amino)butyl)-3-methylbutanamide 149 (51.28 mg, 0.106 mmol, 30.8 % yield) as off white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.73 (d, J = 5.20 Hz, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.18 (d, J = 7.20 Hz, 1H), 7.07 (d, J = 7.60 Hz, 1H), 5.11 (q, J = 5.20 Hz, 1H), 4.39 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 16.80 Hz, 1H), 3.16 (t, J = 6.80 Hz, 4H), 3.02 (d, J = 5.60 Hz, 2H), 2.92 (s, 1H), 2.62 (s, 1H), 2.01 (t, J = 5.60 Hz, 1H), 1.92 (t, J = 11.20 Hz, 3H), 1.42 (d, J = 7.20 Hz, 6H), 1.25 (s, 4H), 0.84 (t, J = 6.00 Hz, 9H). LCMS: 485.3 (M+H), Method: Mobile phase: A: 0.1% FA in H2O; Mobile phase: B: ACN; Column: Atlantis dC18 (50 × 4.6 mm) 5 μm; Column: Atlantis dC18 (50 × 4.6 mm) 5 μm; Flow Rate: 1.5 ml / min, Rt (min): 2.252, Area %: 99.867. HPLC: Method: Mobile phase A: 0.1% TFA in water; Mobile phase D: ACN; Column: XBridge C8(50 × 4.6) mm, 3.5 μm; Flow rate: 2.0 ml / min, Rt (min): 3.324 min, Area %: 99.501.

[0430] Compound 150

[0431] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)(pentyl)amino)butyl)- 3,3-dimethylbutanamide To a stirred solution of 3,3-dimethylbutanoic acid 150a (39.9 mg, 0.343 mmol, 1 equiv) in DMF (3 ml) were added HATU (196 mg, 0.515 mmol, 1.5 equiv) and DIPEA (177 mg, 1.373 mmol, 4 equiv) at 0 °C, followed by addition of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2- yl)piperidine-2,6-dione, HCl 47 (150 mg, 0.343 mmol, 1 equiv) and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as monitored by UPLC), reaction mixture was purified by reverse-phase column chromatography (Grace column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions were lyophilised to afford give N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino) butyl)-3,3-dimethylbutanamide 150 (40.2 mg, 0.080 mmol, 23.28 % yield) as off white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 7.69 (d, J = 5.20 Hz, 1H), 7.38 (t, J = 5.60 Hz, 1H), 7.21 (t, J = 6.00 Hz, 1H), 7.11 (s, 1H), 5.14-5.08 (m, 1H), 4.43-4.27 (m, 2H), 3.18 (d, J = 6.00 Hz, 4H), 3.01 (d, J = 4.80 Hz, 3H), 2.62 (s, 1H), 2.02 (d, J = 6.00 Hz, 1H), 1.91 (d, J = 5.60 Hz, 2H), 0.92 (d, J = 5.20 Hz, 9H), 0.84 (d, J = 5.60 Hz, 3H). LCMS: 499.3 (M+H), Method: Mobile phase: A: 0.1% FA in H2O; Mobile phase: B: ACN; Column: Atlantis dC18 (50 × 4.6 mm) 5 μm; Rt (min): 2.340 min, Area %: 99.116. HPLC: Method: Mobile phase A:0 .1%TFA in water; Mobile phase D: ACN; Column: XBridge C8(50 × 4.6) mm, 3.5 μm; Rt (min): 3.570, Area %: 98.021.

[0432] Compound 151

[0433] 2-cyclohexyl-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)butyl)acetamide To a stirred solution of 151a (0.150 g, 0.375 mmol, 1 equiv) in DMF (2 mL) were added DIPEA (0.262 ml, 1.498 mmol, 4 equiv) and HATU (0.214 g, 0.562 mmol, 1.5 equiv) at 0 °C. 3-(4-((4- aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, HCl 47 (0.150 g, 0.375 mmol, 1 equiv) was then added at same temperature and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction (as monitored by LCMS), reaction mixture was purified by reverse-phase column chromatography (Grace® column: C1840 µm, 40 g; flow rate: 20 mL / min; 0.1% aqueous HCOOH / ACN mobile phase). The pure fractions were lyophilized to afford 2-cyclohexyl-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)(pentyl)amino)butyl)acetamide 151 (95.22 mg, 0.180 mmol, 48.2 % yield) as off white solid. LCMS: 525.3 (M+H). Method: Column: Atlantis dC18 (50 × 4.6) 5 μ, Mobile phase: A: 0.1% TFA in H2O B: 0.1% TFA in ACN, Flow Rate: 1.5 ml / min. Rt (min): 1.912; Area% - 99.21. HPLC: 99.40 %, Rt (min): 4.020. Method: Column: X-Bridge C8(50 × 4.6) mm, 3.5 μm, Mobile phase: A: 0.1% TFA in water, Mobile phase: B: ACN, Flow: 2.0 mL / min.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 7.72 (s, 1H), 7.37 (t, J = 7.60 Hz, 1H), 7.18 (d, J = 7.20 Hz, 1H), 7.06 (d, J = 8.40 Hz, 1H), 5.11 (q, J = 4.80 Hz, 1H), 4.39 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 16.80 Hz, 1H), 3.17 (d, J = 6.00 Hz, 4H), 3.01 (d, J = 6.00 Hz, 2H), 2.97-2.83 (m, 1H), 2.01 (t, J = 6.00 Hz, 1H), 1.89 (d, J = 6.80 Hz, 2H), 1.59 (d, J = 8.80 Hz, 6H), 1.42 (d, J = 6.80 Hz, 6H), 1.25 (s, 4H), 1.15 (t, J = 12.40 Hz, 3H), 0.84 (t, J = 7.20 Hz, 5H).

[0434] Hydrochloride Salt Form of Compound 163

[0435] 3-(4-((4-(benzylamino)butyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.HClTo a solution of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.HCl 47 (200 mg, 0.500 mmol, 1 equiv) and benzaldehyde (55.6 mg, 21.97 mmol, 1.05 equiv) in DCM (4 mL) and DMF (1 mL) was added TFA (0.034 ml, 0.430 mmol, 0.9 equiv) and Sodium triacetoxyborohydide (154 mg, 0.750 mmol, 1.5 equiv) was added in portions at 0°C and the reaction mixture was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by UPLC), the reaction mixture was diluted with DCM (20 mL), washed with water (2 x 10 mL), brine (10 mL), dried over anhy. Na2SO4, filtered and concentrated to give the crude product, which was purified by preparatory HPLC Column: XBridge C8 - 150; Methiod: HCl and ACN, flow rate: 20ml / min) to give 3-(4-((4-(benzylamino)butyl)(pentyl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 163 (29 mg, 0.058 mmol, 23.23% yield) as off white solid.1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 9.08 (s, 2H), 7.52 (q, J = 3.60 Hz, 2H), 7.41- 7.45 (m, 4H), 7.26 (s, 2H), 5.12 (q, J = 5.20 Hz, 1H), 4.60-4.20 (m, 2H), 4.09 (t, J = 6.00 Hz, 2H), 3.22 (s, 2H), 2.92-2.87 (m, 3H), 2.63 (t, J = 18.00 Hz, 1H), 2.33 (d, J = 1.60 Hz, 1H), 1.64 (t, J = 7.60 Hz, 2H), 1.45 (d, J = 24.80 Hz, 4H), 1.28-1.21 (m, 4.8H), 0.84 (t, J = 6.80 Hz, 3H). LCMS: 491.2 (M+H), Method: Mobile phase :A :0.1% TFA in H2O; Mobile phase :B: 0.1% TFA in ACN; Column :XBridge C8 (50×4.6 mm) 3.5 μm; Flow Rate :1.5ml / min; Rt (min): 1.852, Area%: 98.144. HPLC: Method: Mobile phase A:0.1%TFA in water, Mobile phase D:CAN; Flow rate:2.0 ml / min; Rt (min): 3.291, Area%: 95.870.

[0436] Hydrochloride Salt Form of Compound 164

[0437] 3-(1-oxo-4-(pentyl(4-(phenethylamino)butyl)amino)isoindolin-2-yl)piperidine- 2,6-dione, HClTo a solution of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.HCl 47 (150 mg, 0.375 mmol, 1 equiv) in DCM (1.5 mL) and DMF (1.5 mL) were added molecular seives (100 mg, 4 Aobeads), 2-phenylacetaldehyde (45.0 mg, 0.375 mmol, 1 equiv) and sodium triacetoxyhydroborate (119 mg, 0.562 mmol, 1.5 equiv) at 0°C. The reaction mixture was warmed to room temperature and stirred for 16 h. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was filtered and the filtrate was lyophilised to give the crude product. The crude product was purified by preparatory HPLC (Column: XBridge C8 - 150; Method: HCl and ACN, flow rate: 20ml / min) to give 3-(1-oxo-4-(pentyl(4- (phenethylamino)butyl)amino)isoindolin-2-yl)piperidine-2,6-dione, HCl (9 mg, 0.016 mmol, 4.37% yield)) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 7.42-7.33 (m, 3H), 7.29-7.22 (m, 4H), 7.12 (d, J = 8.40 Hz, 1H), 5.12 (q, J = 4.80 Hz, 1H), 4.40 (d, J = 16.80 Hz, 1H), 4.29 (d, J = 17.20 Hz, 1H), 3.20 (s, 3H), 3.18 (s, 2H), 2.92 (q, J = 8.80 Hz, 5H), 2.03-2.00 (m, 1H), 1.57 (t, J = 7.20 Hz, 2H), 1.51-1.42 (m, 4H), 1.30-1.22 (m, 5H), 0.84 (t, J = 6.80 Hz, 6H). LCMS: 505.3 (M+H), Method: Mobile phase: A: 0.1%Formic Acid in H2O B: ACN; Column: Atlantis dC18 (50×4.6)5; Flow Rate :1.5ml / min; Rt (min): 1.867, Area%: 98.821. HPLC: Method: Mobile phase A:0.1% FA in water., Mobile phase D: ACN; Column: X Bridge C8(50×4.6) mm,3.5μm, Flow rate:2.0 ml / min; Rt (min): 3.606, Area%: 98.493.

[0438] Hydrochloride Salt Form of Compound 165

[0439] 3-(1-oxo-4-(pentyl(4-((3-phenylpropyl)amino)butyl)amino)isoindolin-2- yl)piperidine-2,6-dione,HClTo a solution of 3-(4-((4-aminobutyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione.HCl 47 (150 mg, 0.375 mmol, 1 equiv) in DCM (1.5 mL) and DMF (1 mL) were added molecular seives (100 mg, 4 Aobeads), 3-phenylpropanal (50.3 mg, 0.375 mmol, 1 equiv) and sodium triacetoxyhydroborate (119 mg, 0.562 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. Upon completion of the reaction (as confirmed by LCMS), the reaction mixture was filtered and the filtrate was lyophilised to give the crude product. The crude product was purified by preparatory HPLC (Column: XBridge C8 - 150; Method: HCl and ACN, flow rate: 20ml / min) to give 3-(1-oxo-4-(pentyl(4-((3- phenylpropyl)amino)butyl)amino)isoindolin-2-yl)piperidine-2,6-dione,HCl (18 mg, 0.031 mmol, 8.21% yield) as white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 8.37 (s, 1H), 7.40 (t, J = 7.60 Hz, 1H), 7.31 (t, J = 7.60 Hz, 2H), 7.21 (q, J = 2.80 Hz, 3H), 7.11 (d, J = 8.40 Hz, 1H), 5.12 (q, J = 5.20 Hz, 1H), 4.39 (d, J = 16.80 Hz, 1H), 4.28 (d, J = 16.40 Hz, 1H), 3.18 (q, J = 6.40 Hz, 4H), 2.89 (q, J = 7.60 Hz, 5H), 2.51 (q, J = 1.60 Hz, 2H), 2.02 (t, J = 5.20 Hz, 1H), 1.87 (t, J = 7.60 Hz, 2H), 1.56-1.43 (m, 5H), 1.29-1.22 (m, 4H), 0.84 (t, J = 6.80 Hz, 6H). LCMS: 519.3 (M+H), Method: Mobile phase: A :0.1%Formic Acid in H2O B: ACN; Column: Atlantis dC18 (50 x 4.6)5 ; Flow Rate :1.5ml / min; Rt (min): 1.911, Area%: 96.329. HPLC: Method: Mobile phase A:0.1% FA in water, Mobile phase D:ACN, Column: XBridge C8(50×4.6) mm,3.5μm, Flow rate:2.0 ml / min, Rt (min): 3.785, Area%: 94.882.

[0440] Hydrochloride Salt Form of Compound 166

[0441] 3-(4-((4-(butylamino)butyl)(pentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6- dione,...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I),wherein R1is C1-C8alkyl, C3-C8alkenyl, C3-C8alkynyl, C3-C8cycloalkyl or C5-C10bicycloalkyl each optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl, optionally substituted C6-C10aryl, C1-C3alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C5-C10bicycloalkyl or optionally substituted C3-C6heterocycloalkyl; X is a bond or –(CH2)n– optionally substituted with one or more halogen, OH, O-C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl or C1-C6alkyl, wherein the C1-C6alkyl group may be taken together with the atom to which it is attached to form a C3-C6spiro alkyl ring, and wherein the –(CH2)n– group may contain 0-1 double bond or triple bond; n is an integer from 1 to 6; A is a bond, C4-C8cycloalkyl, C5-C10bicycloalkyl, C5-C10heterobicycloalkyl or C3-C8heterocycloalkyl each optionally substituted with one of more halogen, OH, O-C1-C3alkyl, CN, C1-C3haloalkyl, C1-C3alkyl or C3-C5cycloalkyl; Y is a bond or a –(CH2)m–; m is an integer of 1 or 2; Z is H or halogen; R2is -NR12R5, -NHC(O)R6, -NHC(O)NR8(R9), -C(O)NHR5, five or six-membered heteroaryl, or C3-C8heterocycloalkyl or C5-C10heterobicycloalkyl ring optionally substituted with one of more halogen, OH, O-C1-C3alkyl, CN, C1-C3haloalkyl, C1-C3alkyl or C3-C5cycloalkyl; R5is H, C1-C5alkyl, C3-C7cycloalkyl, five or six-membered heteroaryl, C5-C10bicycloalkyl, (C3-C6cycloalkyl)-C1-C3alkyl, (C3-C6heterocycloalkyl)-C1-C3alkyl, (C6-C10aryl)-C1-C3alkyl, (C1-C5-heteroaryl)-C1-C3alkyl or C3-C7heterocycloalkyleach optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl, CH3SO2-, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C7heterocycloalkyl or C(O)NR8(R9); R6is C1-C6alkyl, C3-C6cycloalkyl or C3-C6heterocycloalkyl each optionally substituted with one or more halogen, C1-C3haloalkyl, optionally substituted C3-C6cycloalkyl, or NR8(R9); R8and R9are each independently H, substituted C1-C3alkyl or taken together with the nitrogen to which they are attached to form a 4-6 membered heterocyclic ring optionally substituted with one or more halogen or C1-C3haloalkyl; R12is H, C1-C5alkyl, or taken together with R5and the nitrogen to which it is attached to form (i) C3-C8cycloalkyl or heterocycloalkyl ring or (ii) C5-C10bicycloalkyl or heterobicycloalkyl ring, each optionally substituted with one or more halogen, C1-C3haloalkyl, OH, O-(C1-C3alkyl), O-(C1-C3haloalkyl) or CN. each stereocenter in the compound of Formula (I) is independently the R-enantiomer, the S-enantiomer or a mixture of R- and S- enantiomers; and each double bond in the compound of Formula (I) is independently cis or trans, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

2. The compound of claim 1, wherein the compound is represented by Formula (I-a) and X is a bond or –(CH2)n–,or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

3. The compound of claim 2, wherein R1is C1-C8alkyl or C3-C8cycloalkyl each optionally substituted with one or more halogen, OH, NH2, C1-C3alkyl, C1-C3haloalkyl, O-(C1-C3alkyl), optionallysubstituted C6aryl, optionally substituted C3-C8cycloalkyl, optionally substituted C3- C6heterocycloalkyl or optionally substituted C6-C8bicycloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

4. The compound of Claim 2, wherein A is C4-C6cycloalkyl, C4-C6heterocycloalkyl or C5-C7bicycloalkyl each optionally substituted with one or more halogen, OH, C1-C3alkyl or C1-C3haloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

5. The compound of claim 2, wherein Y is a bond or -CH2-, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

6. The compound of claim 2, wherein R5is H, C1-C5alkyl, C3-C6cycloalkyl, 6-membered heteroaryl, C5bicycloalkyl, (C3-C4cycloalkyl)-C1-C2alkyl, (C3-C4heterocycloalkyl)-C1-C2alkyl, (C6aryl)-C1-C2alkyl, (C5heteroaryl)-C1-C2alkyl or C3-C4heterocycloalkyl each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl, CH3SO2- or C(O)NR8(R9); or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

7. The compound of claim 2, wherein R12is H, C1-C5alkyl, or taken together with R5and the nitrogen to which it is attached to form a C3-C8heterocycloalkyl ring optionally substituted with one or more halogen or C1-C3haloalkyl. or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

8. The compound of claim 1, wherein the compound is represented by Formula (I-b) and X is a bond or –(CH2)n–,or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

9. The compound of claim 8, wherein R1is C3-C6alkyl optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

10. The compound of claim 8, wherein A is bond or C4-C6cycloalkyl optionally substituted with one or more halogen, OH, O- C1-C3alkyl, NH2, C1-C3haloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

11. The compound of claim 8, wherein Y is a bond, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

12. The compound of claim 8, wherein R6is C1-C6alkyl, optionally substituted with NR8(R9), or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

13. The compound of claim 1, wherein the compound is represented by Formula (I-c) and X is a bond or –(CH2)n–,or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

14. The compound of claim 13, wherein R1is C1-C6alkyl optionally substituted with optionally substituted C3-C8cycloalkyl or optionally substituted C3-C6heterocycloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

15. The compound of claim 13, wherein A is bond, C4-C6cycloalkyl, C4-C6heterocycloalkyl or C5-C7bicycloalkyl each optionally substituted with one or more halogen, OH, O-C1-C3alkyl, NH2, C1-C3haloalkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

16. The compound of claim 13, wherein Y is a bond, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

17. The compound of claim 13, wherein R5is H or C1-C3alkyl, or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

18. The compound of claim 1, wherein each X and Y is a bond; A is C4-C6cycloalkyl; R1is C1-C3alkyl optionally substituted with optionally substituted C3-C6cycloalkyl; and R2is 5-membered heteroaryl,or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

19. A compound of Formula (I-d),wherein R1is C1-C3alkyl optionally substituted with optionally substituted C3-C6cycloalkyl; A is optionally substituted C4-C6cycloalkyl; R2is C1-C4alkyl or (C3-C4cycloalkyl)-C1-C2alkyl, each optionally substituted with one or more halogen, CN, OH, O-(C1-C3haloalkyl), O-(C1-C3alkyl), C1-C3haloalkyl or CH3SO2-; each stereocenter in the compound of Formula (I-d) is independently the R-enantiomer, the S-enantiomer or a mixture of R- and S- enantiomers; and or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

20. The compound of claim 19, wherein R2is C1-C3alkyl optionally substituted with one or more halogen, O-(C1-C3haloalkyl), O-(C1-C3alkyl) or C1-C3haloalkyl; or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

21. The compound of claim 1 or 19, wherein the compound is for use in degrading or reducing casein kinase 1 alpha (CK1α).

22. The compound of claim 1 or 19, wherein the compound is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

23. The compound of claim 1 or 19, wherein the compound is for use in preventing or treating blood cancer.

24. A pharmaceutical composition comprising: the compound of claim 1 or 19, or the pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof, and optionally a pharmaceutically acceptable excipient or carrier.

25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is for use in degrading or reducing casein kinase 1 alpha (CK1α).

26. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

27. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is for use in preventing or treating blood cancer.

28. The pharmaceutical composition of claim 27, wherein the blood cancer is leukemia, lymphoma, or myeloma.

29. The pharmaceutical composition of claim 28, wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia or acute lymphocytic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), Large granular lymphocytic leukemia, adult T-cell leukemia, chronic eosinophilic leukemia (CEL) and myelodysplastic syndrome (MDS).

30. The pharmaceutical composition of claim 28, wherein the lymphoma is selected from the group consisting of Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL),follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system (CNS) lymphoma and peripheral T-cell lymphoma.

31. The pharmaceutical composition of claim 28, wherein the myeloma is selected from the group consisting of multiple myeloma, light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma and immunoglobulin E (IgE) myeloma.

32. A method of degrading or reducing casein kinase 1 alpha (CK1α) in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

33. A method of inhibiting casein kinase 1 alpha (CK1α) activity in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

34. A method of preventing or treating blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 24.

35. The method of claim 34, wherein the blood cancer is leukemia, lymphoma, or myeloma.

36. The method of claim 35, wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia or acute lymphocytic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), T-cell prolymphocyticleukemia (T-PLL), Large granular lymphocytic leukemia, adult T-cell leukemia, chronic eosinophilic leukemia (CEL) and myelodysplastic syndrome (MDS).

37. The method of claim 35, wherein the lymphoma is selected from the group consisting of Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system (CNS) lymphoma and peripheral T-cell lymphoma.

38. The method of claim 35, the myeloma is selected from the group consisting of multiple myeloma, light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma and immunoglobulin E (IgE) myeloma.

39. A compound of: [Table A]or a pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof.

40. A pharmaceutical composition comprising: the compound of claim 39, or the pharmaceutically acceptable salt, enantiomer, stereoisomer or prodrug thereof, and optionally a pharmaceutically acceptable excipient or carrier.

41. The pharmaceutical composition of claim 40, wherein the pharmaceutical composition is for use in degrading or reducing casein kinase 1 alpha (CK1α).

42. The pharmaceutical composition of claim 40, wherein the pharmaceutical composition is for use in inhibiting casein kinase 1 alpha (CK1α) activity.

43. The pharmaceutical composition of claim 40, wherein the pharmaceutical composition is for use in preventing or treating blood cancer.

44. The pharmaceutical composition of claim 40, wherein the blood cancer is leukemia, lymphoma, or myeloma.

45. The pharmaceutical composition of claim 44, wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia or acute lymphocytic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), Large granular lymphocytic leukemia, adult T-cell leukemia, chronic eosinophilic leukemia (CEL) and myelodysplastic syndrome (MDS).

46. The pharmaceutical composition of claim 44, wherein the lymphoma is selected from the group consisting of Hodgkin’s lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphomas, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system (CNS) lymphoma and peripheral T-cell lymphoma.

47. The pharmaceutical composition of claim 44, wherein the myeloma is selected from the group consisting of multiple myeloma, light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma and immunoglobulin E (IgE) myeloma.

48. A method of degrading or reducing casein kinase 1 alpha (CK1α) in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition of comprising the compound according to claim 39.

49. A method of inhibiting casein kinase 1 alpha (CK1α) activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition of comprising the compound according to claim 39.

50. A method of preventing or treating blood cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition of comprising the compound according to claim 39.

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